Methods of treatment

ABSTRACT

This disclosure features compounds and compositions that are useful in methods of treating coronavirus infections (e.g., useful in methods of treating COVID-19) in a subject in need thereof. The methods include administering to the subject niclosamide compounds (or pharmaceutically acceptable salts and/or co-crystals thereof, e.g., niclosamide). In some embodiments, the niclosamide compounds have one or more properties that include, but are not limited to: a particular purity or a particular particle size. In an aspect, the niclosamide compounds described herein (e.g., niclosamide) can form part of compositions, dosage forms (e.g., unit dosage forms), and the like, which are suitable for respiratory administration (e.g., via inhalation and/or intranasally). In another aspect, the niclosamide compounds described herein (e.g., niclosamide) can form part of compositions, dosage forms (e.g., unit dosage forms), and the like, which are suitable for administration to the GI tract (e.g., orally or rectally such as via enema)).

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/231,716, filed on Apr. 15, 2021, which is a continuation of U.S.application Ser. No. 16/835,307, filed on Mar. 31, 2020, which claimsthe benefit of U.S. Provisional Application No. 62/990,414 filed on Mar.16, 2020; U.S. Provisional Application No. 62/993,688 filed on Mar. 23,2020; and U.S. Provisional Application No. 63/002,324, filed on Mar. 30,2020, each of which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

This disclosure features compounds and compositions that are useful inmethods of treating coronavirus infections (e.g., useful in methods oftreating COVID-19) in a subject in need thereof. The methods includeadministering to the subject niclosamide compounds (or pharmaceuticallyacceptable salts and/or co-crystals thereof, e.g., niclosamide). In someembodiments, the niclosamide compounds have one or more properties thatinclude, but are not limited to: a particular purity (e.g., a chemicalpurity of greater than about 99.0%) or a particular particle size (e.g.,a particular particle size distribution and/or a particular particlesize range and/or a specific surface area range). In an aspect, theniclosamide compounds described herein (e.g., niclosamide) can form partof compositions, dosage forms (e.g., unit dosage forms), and the like,which are suitable for respiratory administration (e.g., via inhalationand/or intranasally). In another aspect, the niclosamide compoundsdescribed herein (e.g., niclosamide) can form part of compositions,dosage forms (e.g., unit dosage forms), and the like, which are suitablefor administration to the GI tract (e.g., orally or rectally such as viaenema)).

BACKGROUND

Coronaviruses are a group of positive-sense single-strand RNA viruses inthe family Coronaviridae in the order Nidovirales. Coronaviruses can befurther classified by genera: alphacoronavirus, betacoronavirus,gammacoronavirus, and deltacoronavirus. Coronaviruses can cause a widerange of disease in both humans and animals, including the common cold.In some cases, coronavirus infection can be more severe. Examples ofcoronaviruses include SARS-CoV (causing Severe Acute RespiratorySyndrome (SARS)), MERS-CoV (Middle East Respiratory Syndrome (MERS),also sometimes called camel flu). In late 2019, human infection by thecoronavirus SARS-CoV-2 (sometimes also called 2019-nCoV) was firstrecorded in Wuhan, China and quickly spread throughout the globe. Thecorresponding outbreak of disease is often called COVID-19 (coronavirusdisease 2019, sometimes also called Wuhan coronavirus).

Cases of COVID-19 can sometimes be asymptomatic, or sometimes presentwith flu-like symptoms such as fever, cough, fatigue, shortness ofbreath, muscle and/or joint pain, sore throat, headache, and/or chills.COVID-19 can have a long incubation period before symptoms appear; theincubation period typically ranges between 1 and 14 days, but has beenreported to be up to 27 days. The reported basic reproduction number,the average number of people an infected person is likely to infect,ranges from about 2 to about 5. The fatality rate of COVID-19 varies bylocation and age of the subject, but on average, it has been reported tobe about 2% to about 3%, with more fatalities occurring in older agegroups. There are no approved specific therapies for COVID-19.

SUMMARY

This disclosure features compounds and compositions that are useful inmethods of treating coronavirus infections (e.g., useful in methods oftreating COVID-19) in a subject in need thereof. The methods includeadministering to the subject niclosamide compounds (or pharmaceuticallyacceptable salts and/or co-crystals thereof, e.g., niclosamide). In someembodiments, the niclosamide compounds have one or more properties thatinclude, but are not limited to: a particular purity (e.g., a chemicalpurity of greater than about 99.0%) or a particular particle size (e.g.,a particular particle size distribution and/or a particular particlesize range and/or a specific surface area range). In an aspect, theniclosamide compounds described herein (e.g., niclosamide) can form partof compositions, dosage forms (e.g., unit dosage forms), and the like,which are suitable for respiratory administration (e.g., via inhalationand/or intranasally). In another aspect, the niclosamide compoundsdescribed herein (e.g., niclosamide) can form part of compositions,dosage forms (e.g., unit dosage forms), and the like, which are suitablefor administration to the GI tract (e.g., orally or rectally such as viaenema)).

In one aspect, this disclosure features a method for treating COVID-19in a subject in need thereof, the method comprising administering aneffective amount of a niclosamide compound, or a pharmaceuticallyacceptable salt thereof, to the subject.

In another aspect, this disclosure features methods useful forpreventing the progression of COVID-19 in a subject (e.g., methods forreducing the likelihood of a subject's developing COVID-19 as well asmethods for reducing or slowing the progression of COVID-19 in asubject, e.g., reducing the likelihood that a subject will experienceone or more severe or life-threating COVID-19 symptoms). In an aspect,this disclosure features methods of reducing the risk of developingCOVID-19 in a subject at risk thereof, the method comprisingadministering an effective amount (e.g., a prophylactically effectiveamount) of a niclosamide compound, or a pharmaceutically acceptable saltthereof, to the subject. In a further aspect, this disclosure featuresmethods of preventing COVID-19 in a subject at risk thereof, the methodcomprising administering an effective amount (e.g., a prophylacticallyeffective amount) of a niclosamide compound, or a pharmaceuticallyacceptable salt thereof, to the subject. In some of the foregoingembodiments, the niclosamide compound is niclosamide.

In another aspect, this disclosure features a method useful for treatingCOVID-19 in a subject in need thereof, the method comprisingadministering an effective amount of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the GI tract of thesubject. In certain embodiments, the method comprises locally (e.g.,topically (e.g., by rectal administration such as via enema rectal gel,rectal foam, rectal aerosol, or suppository (e.g., by enema))administering an effective amount of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the GI tract of thesubject. In certain embodiments, the method comprises orallyadministering an effective amount of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the GI tract of the subject(e.g., in a suspension, table, or pill (e.g., in a pill)).

In another aspect, this disclosure features a method for treating mildCOVID-19 in a subject in need thereof, the method comprisingadministering an effective amount of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the subject. In certainembodiments, the niclosamide compound is administered to the nasalcavity of the subject.

In another aspect, this disclosure features a method for treating severeCOVID-19 in a subject in need thereof, the method comprisingadministering an effective amount of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the subject. In certainembodiments, the niclosamide compound is administered to the lungs ofthe subject.

In another aspect, this disclosure features a method for treatingCOVID-19 in a subject in need thereof, the method comprising orallyadministering an effective amount of niclosamide:

or a pharmaceutically acceptable salt thereof, to the subject.

In another aspect, the disclosure features a method of reducing the riskof developing (e.g., preventing) COVID-19 in a subject at risk thereof,the method comprising administering (e.g., orally administering) aneffective amount of niclosamide:

or a pharmaceutically acceptable salt thereof, to the subject.

In another aspect, this disclosure features a method for clearingpersistent infection in an asymptomatic (COVID-19 asymptomatic)individual who may or may not have previous COVID-19 illness caused bySARS-COV2, the method comprising orally administering an effectiveamount of niclosamide:

or a pharmaceutically acceptable salt thereof, to the subject.

In another aspect, this disclosure features a method of treating asubject having COVID-19, the method comprising: identifying a subjectthat has: (i) a respiratory rate of <30 breaths per min; (ii) an oxygensaturation at rest of >93%; and (iii) a ratio of partial pressure ofarterial oxygen to fractional concentration of oxygen inspired airof >300 mm Hg; and administering to the nasal cavity of the identifiedsubject a treatment that includes a niclosamide compound, or apharmaceutically acceptable salt thereof. In certain embodiments, theniclosamide compound, or a pharmaceutically acceptable salt thereof, isformulated for delivery by inhalation.

In another aspect, this disclosure features a method of treating asubject having COVID-19, the method comprising: identifying a subjectthat has at least one of (i) respiratory distress (i.e., ≥30 breaths permin); (ii) an oxygen saturation at rest of ≤93%; (iii) a ratio ofpartial pressure of arterial oxygen to fractional concentration ofoxygen inspired air of ≤300 mm Hg; and (iv) a severe diseasecomplication; and administering to the lungs of the identified subject atreatment that includes a niclosamide compound, or a pharmaceuticallyacceptable salt thereof. In certain embodiments, the niclosamidecompound, or a pharmaceutically acceptable salt thereof, is formulatedfor delivery by inhalation.

In another aspect, this disclosure features a method for treating severeCOVID-19 in a subject in need thereof, the method comprisingadministering an effective amount of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the GI tract of the subject(e.g., by oral delivery).

In another aspect, this disclosure features a method of treating asubject having COVID-19, the method comprising: (a) identifying asubject having (i) a respiratory rate of <30 breaths per min; (ii) anoxygen saturation at rest of >93%; and (iii) a ratio of partial pressureof arterial oxygen to fractional concentration of oxygen inspired airof >300 mm Hg; (b) administering one or more doses of a niclosamidecompound, or a pharmaceutically acceptable salt thereof, to the nasalcavity of the subject; (c) after (a) and (b), identifying whether thesubject has at least one of: (i) respiratory distress (i.e., ≥30 breathsper min); (ii) an oxygen saturation at rest of ≤93%; (iii) a ratio ofpartial pressure of arterial oxygen to fractional concentration ofoxygen inspired air of ≤300 mm Hg; and (iv) a severe diseasecomplication, e.g., a severe disease complication as described herein;and (d) administering one or more doses of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the lungs of the subject inwhich the subject has at least one of: (i) respiratory distress (i.e.,≥30 breaths per min); (ii) an oxygen saturation at rest of ≤93%; (iii) aratio of partial pressure of arterial oxygen to fractional concentrationof oxygen inspired air of ≤300 mm Hg; and (iv) a severe diseasecomplication; or (e) administering additional doses of the niclosamidecompound, or a pharmaceutically acceptable salt thereof, to the nasalcavity of the subject in which (i) a respiratory rate of <30 breaths permin; (ii) an oxygen saturation at rest of >93%; and (iii) a ratio ofpartial pressure of arterial oxygen to fractional concentration ofoxygen inspired air of >300 mm Hg.

In another aspect, this disclosure features a method of treating asubject having COVID-19, the method comprising: (a) identifying asubject having (i) a respiratory rate of <30 breaths per min; (ii) anoxygen saturation at rest of >93%; and (iii) a ratio of partial pressureof arterial oxygen to fractional concentration of oxygen inspired airof >300 mm Hg; (b) administering one or more doses of a niclosamidecompound, or a pharmaceutically acceptable salt thereof, to the nasalcavity of the subject; (c) after (a) and (b), identifying whether thesubject has at least one of: (i) respiratory distress (i.e., ≥30 breathsper min); (ii) an oxygen saturation at rest of ≤93%; (iii) a ratio ofpartial pressure of arterial oxygen to fractional concentration ofoxygen inspired air of ≤300 mm Hg; and (iv) a severe diseasecomplication; and (d) administering one or more doses of a niclosamidecompound, or a pharmaceutically acceptable salt thereof, to the GI tractof the subject in which the subject has at least one of: (i) respiratorydistress (i.e., ≥30 breaths per min); (ii) an oxygen saturation at restof ≤93%; (iii) a ratio of partial pressure of arterial oxygen tofractional concentration of oxygen inspired air of ≤300 mm Hg; and (iv)a severe disease complication, e.g., a severe disease complication asdescribed herein; or (e) administering additional doses of theniclosamide compound, or a pharmaceutically acceptable salt thereof, tothe nasal cavity of the subject in which (i) a respiratory rate of <30breaths per min; (ii) an oxygen saturation at rest of >93%; and (iii) aratio of partial pressure of arterial oxygen to fractional concentrationof oxygen inspired air of >300 mm Hg.

In another aspect, this disclosure features a method of treating asubject having COVID-19, the method comprising: (a) identifying asubject having (i) a respiratory rate of <30 breaths per min; (ii) anoxygen saturation at rest of >93%; and (iii) a ratio of partial pressureof arterial oxygen to fractional concentration of oxygen inspired airof >300 mm Hg; (b) administering one or more doses of a niclosamidecompound, or a pharmaceutically acceptable salt thereof, to the nasalcavity of the subject; (c) after (a) and (b), identifying whether thesubject has at least one of: (i) respiratory distress (i.e., ≥30 breathsper min); (ii) an oxygen saturation at rest of ≤93%; (iii) a ratio ofpartial pressure of arterial oxygen to fractional concentration ofoxygen inspired air of ≤300 mm Hg; and (iv) a severe diseasecomplication; and (d) administering one or more doses of a niclosamidecompound, or a pharmaceutically acceptable salt thereof, to the GI tractof the subject and administering one or more doses of a niclosamidecompound, or a pharmaceutically acceptable salt thereof, to the lungs ofthe subject in which the subject has at least one of: (i) respiratorydistress (i.e., ≥30 breaths per min); (ii) an oxygen saturation at restof ≤93%; (iii) a ratio of partial pressure of arterial oxygen tofractional concentration of oxygen inspired air of ≤300 mm Hg; and (iv)a severe disease complication, e.g., a severe disease complication asdescribed herein; or (e) administering additional doses of theniclosamide compound, or a pharmaceutically acceptable salt thereof, tothe nasal cavity of the subject in which (i) a respiratory rate of <30breaths per min; (ii) an oxygen saturation at rest of >93%; and (iii) aratio of partial pressure of arterial oxygen to fractional concentrationof oxygen inspired air of >300 mm Hg.

In another aspect, this disclosure features a method of treating asubject having COVID-19, the method comprising: (a) identifying asubject having at least one of (i) respiratory distress (i.e., ≥30breaths per min); (ii) an oxygen saturation at rest of ≤93%; (iii) aratio of partial pressure of arterial oxygen to fractional concentrationof oxygen inspired air of ≤300 mm Hg; and (iv) a severe diseasecomplication; (b) administering one or more doses of a niclosamidecompound, or a pharmaceutically acceptable salt thereof, to the lungs ofthe subject; (c) after (a) and (b), identifying whether the subject has(i) a respiratory rate of <30 breaths per min; (ii) an oxygen saturationat rest of >93%; and (iii) a ratio of partial pressure of arterialoxygen to fractional concentration of oxygen inspired air of >300 mm Hg;and (d) administering one or more doses of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the nasal cavity of thesubject in which the subject has (i) a respiratory rate of <30 breathsper min; (ii) an oxygen saturation at rest of >93%; and (iii) a ratio ofpartial pressure of arterial oxygen to fractional concentration ofoxygen inspired air of >300 mm Hg; or (e) administering additional dosesof the niclosamide compound, or a pharmaceutically acceptable saltthereof, to the lungs of the subject in which i(i) respiratory distress(i.e., ≥30 breaths per min); (ii) an oxygen saturation at rest of ≤93%;(iii) a ratio of partial pressure of arterial oxygen to fractionalconcentration of oxygen inspired air of ≤300 mm Hg; and (iv) a severedisease complication.

In another aspect, this disclosure features methods that includeadministering a co-crystal that includes a niclosamide compound (e.g.,niclosamide having any one or more or the properties described herein),or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable coformer. In some embodiments, the cocrystal has a reducedparticle size as described anywhere herein (e.g., the cocrystal itselfcan be reduced to have the reduced particle size range, and/or thereduced particle size distribution described herein for niclosamidecompounds).

In some embodiments, niclosamide compounds (e.g., niclosamide) describedherein having a reduced particle size can be readily and efficientlyadministered, such that the resultant local bioavailability of theadministered niclosamide compounds (e.g., niclosamide) in therespiratory tract is relatively high (e.g., as compared with resultantsystemic bioavailability of the administered niclosamide compounds(e.g., niclosamide)). Local (non-systemic) administration of theniclosamide compounds (e.g., niclosamide) at a desired area of treatment(e.g., respiratory tract, e.g., upper respiratory tract or lowerrespiratory tract, e.g., lungs) significantly reduces the likelihoodthat a patient will experience systemic toxicities associated with somecurrent standards of care.

In another aspect, provided herein is a method for clearing persistentinfection in an asymptomatic individual who may or may not have previousCOVID-19 illness caused by SARS-COV2, the method comprisingadministering an effective amount of niclosamide:

or a pharmaceutically acceptable salt thereof, to the subject.

Accordingly, in some embodiments, the niclosamide compounds (e.g.,niclosamide) described herein (e.g., reduced particle size niclosamidecompounds (e.g., niclosamide)) can provide targeted delivery of theniclosamide compound (e.g., niclosamide) to certain regions of therespiratory tract (e.g., upper respiratory tract or lower respiratorytract (e.g., lungs)). In some embodiments, administration (e.g.,respiratory administration (e.g., via inhalation)) of a niclosamidecompound (e.g., niclosamide) described herein to a subject moreefficiently produces a local concentration of the niclosamide compound(e.g., niclosamide) at a site where treatment is needed (e.g.,respiratory tract, lower respiratory tract e.g., lungs) of a respiratoryinfection associated with COVID-19. Moreover, the foregoing canpotentially be achieved using a lower dosage with the reduced particlesize niclosamide compounds (e.g., niclosamide) described herein.

In some embodiments, the methods and compositions described herein aresuitable for use in combination therapy with various other therapeuticregimens.

Embodiments can include one or more of the following features.

The niclosamide compound can have the following formula:

The methods as described herein can comprise administering the effectiveamount of the niclosamide compound, or a pharmaceutically acceptablesalt thereof, to the respiratory system of the subject. For example, themethods can comprise locally and/or topically (e.g., locally andtopically) administering an effective amount of the niclosamidecompound, or a pharmaceutically acceptable salt thereof, to therespiratory system of the subject.

The methods as described herein can comprise administering the effectiveamount of the niclosamide compound, or a pharmaceutically acceptablesalt thereof, to the lungs of the subject. For example, the methods asdescribed herein can comprise locally and/or topically (e.g., locallyand topically) administering an effective amount of the niclosamidecompound, or a pharmaceutically acceptable salt thereof, to the lungs ofthe subject.

The methods as described herein can comprise administering aprophylactically effective amount of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the subject (e.g., locallyand/or topically (e.g., to the lungs of the subject)).

The subject can be unresponsive to treatment with remdesivir.

The niclosamide compound, or a pharmaceutically acceptable salt thereof,can be administered by inhalation.

The method can comprise administering (e.g., orally administering)niclosamide.

The niclosamide, or a pharmaceutically acceptable salt thereof (e.g.,niclosamide), can be administered by tablet or pill.

The method can comprise orally administering the niclosamide, or apharmaceutically acceptable salt thereof, as a pharmaceuticalcomposition, wherein the pharmaceutical composition is capable of localdelivery to the small intestine.

The method can comprise orally administering the niclosamide, or apharmaceutically acceptable salt thereof, as a pharmaceuticalcomposition, wherein the pharmaceutical composition is capable of localdelivery to the GI tract (e.g., lower GI tract).

The subject can be asymptomatic; or the subject can exhibit one or moresymptoms selected from the group consisting of fever, cough, fatigue,shortness of breath, muscle and/or joint pain, sore throat, headache,and/or chills (e.g., fever, cough, and shortness of breath). Forexample, the one or more symptoms can appear from 2-14 days after thesubject's exposure to coronavirus.

The subject can be a human. For example, the subject can be 60 years ofage or older; and/or subject can suffer from one or more preexistingmedical conditions selected from the group consisting of lung disease,cardiovascular disease, and diabetes. The subject can be an individualthat has travelled to an area having confirmed cases of COVID-19 or hasbeen in relatively close contact (e.g., less than 6 feet apart) fromsuch an individual (e.g., a family member or co-worker, commuter,business patron).

The subject can be a subject at risk of developing COVID-19.

The subject at risk of developing COVID-19 can be a healthcare worker(e.g., emergency room physician or nurse, first responder). The subject(e.g., male or female) at risk of developing COVID-19 can be 60 years ofage or older (e.g., 65, 70, 75, 80, 85, 90 years of age or older). Thesubject at risk of developing COVID-19 can suffer from one or morepreexisting medical conditions selected from the group consisting oflung disease, cardiovascular disease, and diabetes. The subject at riskof developing COVID-19 can be a resident of an assisted living facilityor nursing home, a patient in a hospital for an unrelated treatment(i.e., not related to treatment for COVID-19), or a person incarceratedor working in a prison or jail setting. The subject at risk ofdeveloping COVID-19 can be unresponsive to treatment with remdesivir.The subject at risk of developing COVID-19 may have been exposed to thevirus or presumed to have been exposed to the virus. The subject can bean individual that has travelled or plans to travel to an area havingconfirmed cases of COVID-19 or has been or plans to be in relativelyclose contact (e.g., less than 6 feet apart) from such an individual(e.g., a family member or co-worker, commuter, business patron).

The subject can be 60 years of age or older.

The subject can suffer from one or more preexisting medical conditionsselected from the group consisting of lung disease, cardiovasculardisease, cancer, colitis, hypertension, and an endocrine disease.

The compound can be administered prior to exposure to the coronavirus orimmediately after exposure or presumed exposure to the coronavirus.

The method can further comprise one or more of the following:quarantine, self-quarantine, social distancing, frequent hand washing,and frequent environmental sanitization.

The subject can exhibit a digestive symptom. For example, the subjectcan exhibit a symptom selected from the group consisting of a lack orloss of appetite, diarrhea, vomiting, abdominal pain, a digestivedisease, and combinations thereof. For example, the subject can exhibita symptom selected from the group consisting of lack or loss ofappetite, diarrhea, vomiting, abdominal pain, and combinations thereof.As a non-limiting example, the subject can exhibit a symptom selectedfrom the group consisting of diarrhea.

The subject exhibits no accompanying respiratory symptom.

The subject can exhibit an accompanying respiratory symptom.

The subject can suffer from one or more preexisting medical conditionsselected from the group consisting of lung disease, cardiovasculardisease, cancer, hypertension, and an endocrine disease. For example,the subject can suffer from, or can be predisposed to suffer fromcolitis (e.g., an autoimmune colitis; an inflammatory bowel disease;Crohn's disease; iatrogenic autoimmune colitis; or a condition selectedfrom the group consisting of colitis induced by treatment with adoptivecell therapy, colitis associated by one or more alloimmune diseases,collagenous colitis, lymphocytic colitis, C. difficile colitis, andmicroscopic colitis).

The digestive symptom can appears from 2-14 days after the subject'sexposure to coronavirus.

The subject can have mild COVID-19. For example, the subject can have:(i) a respiratory rate of ≤30 breaths per min (e.g., <30); (ii) anoxygen saturation at rest of ≥93% (e.g., >93%); and (iii) a ratio ofpartial pressure of arterial oxygen to fractional concentration ofoxygen inspired air of ≥300 mm Hg (e.g., >300). For example, the subjecthaving mild COVID-19 does not have a severe disease complication. Thesubject can have a low viral load (e.g., a sample (e.g., anasopharyngeal swab sample, an oropharyngeal swab sample, a sputumsample, a bronchoalveolar lavage sample, a nasopharyngeal aspirate, anasopharyngeal wash, a nasal aspirate, a nasal wash, or a lowerrespiratory tract aspirate) from the subject can have a ΔCt of about 3to about 15).

The subject can have severe COVID-19. For example, the subject can have:at least one of: (i) respiratory distress (i.e., ≥30 breaths per min);(ii) an oxygen saturation at rest of ≤93%; (iii) a ratio of partialpressure of arterial oxygen to fractional concentration of oxygeninspired air of ≤300 mm Hg; and (iv) a severe disease complication. Forexample, the subject can have high viral load (e.g., a sample (e.g., anasopharyngeal swab sample, an oropharyngeal swab sample, a sputumsample, a bronchoalveolar lavage sample, a nasopharyngeal aspirate, anasopharyngeal wash, a nasal aspirate, a nasal wash, or a lowerrespiratory tract aspirate) from the subject has a ΔCt of about 2 toabout −10.

The compound can be administered to the subject at risk of developingCOVID-19 prior to exposure to the virus or prior to presumed exposure tothe virus (e.g., prior to contact with one or more individuals having orpresumed to have COVID-19 and/or prior to contact with one or morearticles contaminated with the virus). The compound can be administeredimmediately after or shortly after exposure or presumed exposure to thevirus.

The methods described herein can further comprise one or more of thefollowing: quarantine, self-quarantine, social distancing, frequent handwashing, and frequent environmental sanitization.

The methods herein can further comprises administering a secondtherapeutic agent. The second therapeutic agent can be an antiviralagent. The second therapeutic agent can be selected from the groupconsisting of azithromycin, remdesivir, colchicine, hydroxychloroquine,colchicine, and chloroquine.

The niclosamide compound can have a chemical purity of greater thanabout 99.0%.

The compound can have a reduced particle size range. For example, thecompound can have a particle size range of from about 0.1 μm to about 30μm, such as a particle size range of from about 0.1 μm to about 20 μm(e.g., a particle size range of from about 0.1 μm to about 10 μm).

The compound can have a particle size distribution D(0.9) of from about1.0 μm to about 15.0 μm, such as a particle size distribution D(0.9) offrom about 1.0 μm to about 10.0 μm (e.g., a particle size distributionD(0.9) of from about 6.0 μm to about 8.0 μm; or a particle sizedistribution D(0.9) of from about 2.2 μm to about 3.2 μm).

The compound can have a particle size distribution D(0.1) of from about0.1 μm to about 1.5 μm, such as a particle size distribution D(0.1) offrom about 0.1 μm to about 1.0 μm (e.g., a particle size distributionD(0.1) of from about 0.3 μm to about 0.9 μm).

The compound can have a particle size distribution D(0.5) of from about0.5 μm to about 6.0 μm, such as a particle size distribution D(0.5) offrom about 1.0 μm to about 4.0 μm (e.g., a particle size distributionD(0.5) of from about 1.0 μm to about 2.0 μm; or a particle sizedistribution D(0.5) of from about 2.5 μm to about 3.5 μm).

The compound can have a particle size distribution D(0.9) of from about1.0 μm to about 10.0 μm, a particle size distribution D(0.5) of fromabout 1.0 μm to about 4.0 μm, and a particle size distribution D(0.1) offrom about 0.1 μm to about 1.0 μm.

The compound can have a particle size distribution D(0.9) of from about6.0 μm to about 8.0 μm, a particle size distribution D(0.5) of fromabout 1.0 μm to about 4.0 μm, and a particle size distribution D(0.1) offrom about 0.3 μm to about 0.9 μm.

The compound can have a particle size distribution D(0.9) of from about2.2 μm to about 3.2 μm, a particle size distribution D(0.5) of fromabout 1.0 μm to about 4.0 μm, and a particle size distribution D(0.1) offrom about 0.3 μm to about 0.9 μm.

The compound can have a chemical purity of greater than about 99.0%, aparticle size distribution D(0.9) of from about 1.0 μm to about 10.0 μm,a particle size distribution D(0.5) of from about 1.0 μm to about 4.0μm, and a particle size distribution D(0.1) of from about 0.1 μm toabout 1.0 μm.

The compound can have a chemical purity of greater than about 99.0%, aparticle size distribution D(0.9) of from about 6.0 μm to about 8.0 μm,a particle size distribution D(0.5) of from about 1.0 μm to about 4.0μm, and a particle size distribution D(0.1) of from about 0.3 μm toabout 0.9 μm.

The compound can have a chemical purity of greater than about 99.0%, aparticle size distribution D(0.9) of from about 2.2 μm to about 3.2 μm,a particle size distribution D(0.5) of from about 1.0 μm to about 4.0μm, and a particle size distribution D(0.1) of from about 0.3 μm toabout 0.9 μm.

The compound can have a specific surface area of from about 5 m²/g toabout 10 m²/g.

[A1] The compound can have a chemical purity of greater than about99.0%, a particle size range of from about 0.1 μm to about 30 μm, aparticle size distribution D(0.9) of from about 1.0 μm to about 10.0 μm,a particle size distribution D(0.5) of from about 1.0 μm to about 4.0μm, and a particle size distribution D(0.1) of from about 0.1 μm toabout 1.0 μm.

[B1] The compound can have a chemical purity of greater than about99.0%, a particle size range of from about 0.1 μm to about 30 μm, aparticle size distribution D(0.9) of from about 6.0 μm to about 8.0 μm,a particle size distribution D(0.5) of from about 1.0 μm to about 4.0μm, and a particle size distribution D(0.1) of from about 0.3 μm toabout 0.9 μm.

[C1] The compound can have a chemical purity of greater than about99.0%, a particle size range of from about 0.1 μm to about 30 μm, aparticle size distribution D(0.9) of from about 2.2 μm to about 3.2 μm,a particle size distribution D(0.5) of from about 1.0 μm to about 4.0μm, and a particle size distribution D(0.1) of from about 0.3 μm toabout 0.9 μm.

In certain embodiments of [A1], [B1], and/or [C1] supra, the compoundhas a particle size distribution D(0.5) of from about 2.5 μm to about3.5 μm.

In certain embodiments of [A1], [B1], and/or [C1] supra, the compoundhas a particle size distribution D(0.5) of from about 1.0 μm to about2.0 μm.

In certain embodiments of [A1], [B1], and/or [C1] supra, the compoundhas a chemical purity of greater than about 99.5%; or a chemical purityof greater than about 99.7%; or a chemical purity of greater than about99.8%.

In certain embodiments of [A], [B], and/or [C] supra, the compound has aspecific surface area of from about 5 m²/g to about 10 m²/g.

The niclosamide compound can be administered (via respiratoryadministration) as a pharmaceutical composition, wherein thepharmaceutical composition is capable of local delivery to therespiratory tract. For example, the pharmaceutical composition cancomprises one or more pharmaceutically acceptable excipients thatchemically and/or structurally predispose the composition for deliveryof the niclosamide compound, or a pharmaceutically acceptable saltthereof, to the upper respiratory tract (e.g., nose and nasal passages);and or lower respiratory tract (e.g., the lungs).

For example, the niclosamide compound, or a pharmaceutically acceptablesalt thereof can be administered to the nasal cavity of the subject,wherein the niclosamide compound, or a pharmaceutically acceptable saltthereof, is formulated as an intranasal spray, ointment, or gel. Asanother non-limiting example, the niclosamide compound, or apharmaceutically acceptable salt thereof can be administered to thelungs of the subject, wherein the niclosamide compound, or apharmaceutically acceptable salt thereof, is formulated for delivery byinhalation.

The niclosamide compound can be administered (orally or rectally) as apharmaceutical composition, wherein the pharmaceutical composition iscapable of local delivery to the digestive or GI tract. For example, thepharmaceutical composition can comprises one or more pharmaceuticallyacceptable excipients that chemically and/or structurally predispose thecomposition for delivery of the niclosamide compound, or apharmaceutically acceptable salt thereof, to e.g., the lower GI tract orthe colon (e.g., ascending colon and/or transverse colon and/or distalcolon and/or small intestine (e.g., ileum)).

For example, the niclosamide compound, or a pharmaceutically acceptablesalt thereof can be administered to the GI tract of the subject, whereinthe niclosamide compound, or a pharmaceutically acceptable salt thereof,is formulated as an oral composition

In one aspect, a cocrystal is provided, which includes: (i) niclosamidecompound, such as niclosamide or a pharmaceutically acceptable saltand/or hydrate thereof; and (ii) one or more pharmaceutically acceptablecoformers. In some embodiments, the cocrystal has a reduced particlesize as described anywhere herein. In embodiments, the cocrystalcoformers can include any coformers described herein, including secondtherapeutic agents as described above and anywhere herein.

Definitions

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below. Generally, the nomenclature used herein andthe laboratory procedures in organic chemistry, medicinal chemistry, andpharmacology described herein are those well-known and commonly employedin the art. Unless defined otherwise, all technical and scientific termsused herein generally have the same meaning as commonly understood byone of ordinary skill in the art to which this disclosure belongs. Eachof the patents, applications, published applications, and otherpublications that are mentioned throughout the specification and theattached appendices are incorporated herein by reference in theirentireties.

The term “niclosamide compound” or “niclosamide compounds” includeniclosamide as well as niclosamide analogs described in WO 2017/040864,which is incorporated herein by reference in its entirety. In someembodiments, the niclosamide compound is niclosamide.

“Niclosamide” refers to a compound having the following chemicalstructure:

Niclosamide is known by the IUPAC designation:2,5-dichloro-4′-nitrosalicylanilide and by the CAS designation: CAS:5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide. Niclosamide hasa relatively low water solubility at about from 5-8 mg/L at 20° C., issparingly soluble in ether, ethanol and chloroform, and is soluble inacetone. The ethanolamine salt dissolves in distilled water 180-280 mg/Lat 20° C.

Niclosamide (5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydrobenzamide) is ahalogenated salicylanilide that belongs to a group of medicines known asanthelmintics. Anthelmintics are medicines used in the treatment of worminfections. Niclosamide, which has low systemic bioavailabilty and anexcellent safety profile, is used to treat broad or fish tapeworm, dwarftapeworm, and beef tapeworm infections. It is believed that niclosamideinhibits oxidative phosphorylation and stimulates adenosinetriphosphatase activity in the mitochondria of cestodes (e.g.,tapeworm), killing the scolex and proximal segments of the tapeworm bothin vitro and in vivo (see, Li, Y., et al., Cancer Lett. 2014 349, 8-14).

Niclosamide is available in a various salt or solvated forms. Theseinclude, but are not limited to, the ethanolamine salt known by theIUPAC; designation 5-chloro-salicyl-(2-chloro-4-nitro) anilide2-aminoethanol salt or the CAS designation5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide with2-aminoethanol (1:1)—see, e.g., US 2013/0231312; the piperazine saltknown by the IUPAC designation 5-chloro-salicyl-(2-chloro-4-nitro)anilide piperazine salt or the CAS designation5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide with piperazine(2:1); and niclosamide monohydrate known by the IUPAC designation5-chloro-salicyl-(2-chloro-4-nitro) anilide monohydrate or the CASdesignation 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide withmonohydrate (1:1).

Niclosamide is commercially available in a variety of formulationsincluding; but not limited to BAYER 73®, BAYER 2353®, BAYER 25 648®,BAYLUSCID®, BAYLUSCIDE®, CESTOCID®, CLONITRALID, DICHLOSALE®, FENASAL®,HL 2447®, IOMESAN®, IOMEZAN®, LINTER®, MANOSIL®, NASEMO®, NICLOSAMID®,PHENASAL®, TREDEMINE®, SLLQUI®, VERMITID®, VERMITIN®, YOMESAN®, and thelike.

The terms “respiratory tract” and “respiratory system” refer to theorgans that are involved in breathing: nose, throat, larynx, trachea,bronchi, and lungs.

The term “lower respiratory tract” refers to the part of the respiratorysystem including the portion of the larynx below the vocal folds,trachea, bronchi, and lungs.

The term “upper respiratory tract” refers to the part of the respiratorysystem including the nose and nasal passages, paranasal sinuses, thepharynx, and the portion of the larynx above the vocal folds (cords).

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

“API” refers to an active pharmaceutical ingredient (e.g., niclosamidecompound, e.g., niclosamide).

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of a chemical entity (e.g., acompound exhibiting activity as a mitochondrial uncoupling agent or apharmaceutically acceptable salt and/or hydrate and/or cocrystalthereof; e.g., a compound, such as niclosamide or a pharmaceuticallyacceptable salt and/or hydrate and/or cocrystal thereof; e.g., acompound, such as a niclosamide analog, or a pharmaceutically acceptablesalt and/or hydrate and/or cocrystal thereof) being administered whichwill relieve to some extent one or more of the symptoms of the diseaseor condition being treated. The result includes reduction and/oralleviation of the signs, symptoms, or causes of a disease, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic uses is the amount of the composition comprisinga compound as disclosed herein required to provide a clinicallysignificant decrease in disease symptoms. An appropriate “effective”amount in any individual case is determined using any suitabletechnique, such as a dose escalation study.

The term “excipient” or “pharmaceutically acceptable excipient” means apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, carrier, solvent, or encapsulatingmaterial. In one embodiment, each component is “pharmaceuticallyacceptable” in the sense of being compatible with the other ingredientsof a pharmaceutical formulation, and suitable for use in contact withthe tissue or organ of humans and animals without excessive toxicity,irritation, allergic response, immunogenicity, or other problems orcomplications, commensurate with a reasonable benefit/risk ratio. See,e.g., Remington: The Science and Practice of Pharmacy, 21st ed.;Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook ofPharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; ThePharmaceutical Press and the American Pharmaceutical Association: 2009;Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation,2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In certain instances, pharmaceuticallyacceptable salts are obtained by reacting a compound described herein,with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. In some instances,pharmaceutically acceptable salts are obtained by reacting a compoundhaving acidic group described herein with a base to form a salt such asan ammonium salt, an alkali metal salt, such as a sodium or a potassiumsalt, an alkaline earth metal salt, such as a calcium or a magnesiumsalt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts withamino acids such as arginine, lysine, and the like, or by other methodspreviously determined. The pharmacologically acceptable salt is notspecifically limited as far as it can be used in medicaments. Examplesof a salt that the compounds described herein form with a base includethe following: salts thereof with inorganic bases such as sodium,potassium, magnesium, calcium, and aluminum; salts thereof with organicbases such as methylamine, ethylamine and ethanolamine; salts thereofwith basic amino acids such as lysine and ornithine; and ammonium salt.The salts may be acid addition salts, which are specifically exemplifiedby acid addition salts with the following: mineral acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, and phosphoric acid:organic acids such as formic acid,acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid,fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid,citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic aminoacids such as aspartic acid and glutamic acid.

The term “pharmaceutical composition” refers to a mixture of a compounddescribed herein with other chemical components (referred tocollectively herein as “excipients”), such as carriers, stabilizers,diluents, dispersing agents, suspending agents, and/or thickeningagents. The pharmaceutical composition facilitates administration of thecompound to an organism.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat,rabbit, rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human.

The terms “treat,” “treating,” and “treatment,” in the context oftreating a disease or disorder, are meant to include alleviating orabrogating a disorder, disease, or condition, or one or more of thesymptoms associated with the disorder, disease, or condition; or toslowing the progression, spread or worsening of a disease, disorder orcondition or of one or more symptoms thereof. Often, the beneficialeffects that a subject derives from a therapeutic agent do not result ina complete cure of the disease, disorder or condition. In someembodiments, the terms “treat,” “treating,” and “treatment,” includevirologically curing a viral disorder, disease, or condition; reducingviral shedding; decreasing viral RNA load (e.g., a measured by PCR);reducing the length of stay in a hospital; reducing the length of stayin an infectious disease unit and/or intensive care unit; or slowing(including stopping) the progression/development of respiratory (orother serious) symptoms.

The details of one or more embodiments of the invention are set forth inthe description below. Other features, objects, and advantages of theinvention will be apparent from the description and drawings, and fromthe claims.

DETAILED DESCRIPTION

This disclosure features niclosamide compounds (or pharmaceuticallyacceptable salts and/or co-crystals thereof, e.g., niclosamide), havingone or more properties that include, but are not limited to: aparticular purity (e.g., a chemical purity of greater than about 99.0%)or a particular particle size (e.g., a particular particle sizedistribution and/or a particular particle size range and/or a specificsurface area range) which are useful e.g., in the treatment ofinfections caused by coronaviruses (e.g., treatment of COVID-19). In anaspect, the niclosamide compounds described herein (e.g., niclosamide)can form part of compositions, dosage forms (e.g., unit dosage forms),and the like, which are suitable for respiratory administration (e.g.,inhalation). This disclosure also features methods of making and usingthe same.

Methods of Treatment

In one aspect, provided herein is a method for treating COVID-19 in asubject in need thereof, the method comprising administering aneffective amount of a niclosamide compound, or a pharmaceuticallyacceptable salt thereof, to the subject.

In some embodiments of the methods herein, the subject is asymptomatic.

In some embodiments of the methods herein, the subject exhibits one ormore symptoms selected from the group consisting of fever, cough,fatigue, shortness of breath (dyspnea), muscle and/or joint pain, sorethroat, headache, conjunctivitis, diarrhea, lack or loss of appetite,vomiting, abdominal pain, and/or chills. In certain of theseembodiments, the subject exhibits one or more symptoms selected from thegroup consisting of fever, cough, and shortness of breath. In someembodiments, the subject exhibits one or more digestive symptoms (e.g.,extra-pulmonary symptoms) selected from the group consisting ofdiarrhea, lack or loss of appetite, vomiting, and abdominal pain.

COVID-19 may cause digestive symptoms for several reasons. For example,SARS-CoV-2 can invade the human body by binding to the human angiotensinconverting enzyme 2 (ACE-2) receptor, which can liver tissue injury;SARS-CoV-2 can indirectly or directly damage the digestive systemthrough an inflammatory response; SARS-CoV-2 may cause disorders of theintestinal flora; and changes in the composition and function of thedigestive tract flora can affect the respiratory tract through thecommon mucosal immune system, and respiratory tract flora disorders alsoaffect the digestive tract through immune regulation (e.g., SARS-CoV-2may affect the gut-lung axis). See, e.g., Pan et al. ClinicalCharacteristics of COVID-19 Patients with Digestive Symptoms in Hubei,China: A Descriptive, Cross-Sectional, Multicenter Study. Am. J.Gastroenterol 2020 Mar. 19; [EPub Ahead of Print].

Accordingly, also provided herein is a method for treating one or moredigestive symptoms in a subject having COVID-19, the method comprisingadministering an effective amount of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the subject. In someembodiments, the one or more digestive symptoms are the result ofautoimmune colitis. For example, the autoimmune colitis can be theresult of inflammation in the GI tract. In some embodiments, theautoimmune colitis is the result of overresponsiveness and/orhyperreactivity of the subject's immune system to SARS-CoV-2.

In some embodiments of the methods herein, the one or more symptomsappear from 2-14 (e.g., 2-3 days, 4-5 days, 6-10 days, or 11-14 days)days after the subject's exposure to coronavirus.

In some embodiments, the subject is a subject at risk. In certainembodiments, the subject is 60 years of age or older. In certainembodiments, the subject suffers from one or more preexisting medicalconditions selected from the group consisting of lung disease,cardiovascular disease, and diabetes. In certain embodiments, thesubject is unresponsive to treatment with remdesivir.

In another aspect, provided herein is a method of reducing the risk ofdeveloping COVID-19 in a subject at risk thereof, the method comprisingadministering an effective amount (e.g., a prophylactically effectiveamount) of a niclosamide compound, or a pharmaceutically acceptable saltthereof, to the subject.

In certain embodiments, the subject at risk of developing COVID-19 is ahealthcare worker (e.g., emergency room physician or nurse, firstresponder).

In certain embodiments, the subject at risk of developing COVID-19 is 60years of age or older.

In certain embodiments, the subject at risk of developing COVID-19suffers from one or more preexisting medical conditions selected fromthe group consisting of lung disease, cardiovascular disease, anddiabetes.

In certain embodiments, the subject at risk of developing COVID-19 is aresident of an assisted living facility or nursing home, a patient in ahospital for an unrelated treatment (i.e., not related to treatment forCOVID-19), or a person incarcerated or working in a prison or jailsetting.

In certain embodiments, the subject at risk of developing COVID-19 isunresponsive to treatment with remdesivir.

In certain embodiments, the subject at risk of developing COVID-19 hasbeen exposed to the virus or presumed to have been exposed to the virus.

In certain embodiments, the compound is administered prior to exposureto the virus or prior to presumed exposure to the virus (e.g., prior tocontact with one or more individuals having or presumed to have COVID-19and/or prior to contact with one or more articles contaminated with thevirus). For example, the compound can be administered immediately afteror shortly after exposure or presumed exposure to the virus.

In another aspect, provided herein is a method for treating COVID-19 ina subject in need thereof, the method comprising orally administering aneffective amount of niclosamide:

or a pharmaceutically acceptable salt thereof, to the subject.

In certain of these embodiments, the method comprises administeringniclosamide.

In certain embodiments, subject exhibits a digestive symptom. In certainembodiments, the subject exhibits a symptom selected from the groupconsisting of a lack or loss of appetite, diarrhea, vomiting, abdominalpain, a digestive disease, and combinations thereof. In certainembodiments, the subject exhibits a symptom selected from the groupconsisting of lack or loss of appetite, diarrhea, vomiting, abdominalpain, and combinations thereof. As a non-limiting example of theforegoing embodiments, the subject exhibits a symptom selected from thegroup consisting of diarrhea.

In certain embodiments, the subject does not exhibit an accompanyingrespiratory symptom. In certain other embodiments, subject exhibits anaccompanying respiratory symptom.

In certain embodiments, the subject suffers from one or more preexistingmedical conditions selected from the group consisting of lung disease,cardiovascular disease, cancer, hypertension, and an endocrine disease.

In certain embodiments, the subject suffers from, or is predisposed tosuffer from colitis.

In certain embodiments, the colitis is an autoimmune colitis. In certainembodiments, the colitis is an inflammatory bowel disease. In certainembodiments, the colitis is ulcerative colitis or Crohn's disease. Incertain embodiments, the colitis is iatrogenic autoimmune colitis. Incertain embodiments, the colitis is selected from the group consistingof colitis induced by treatment with adoptive cell therapy, colitisassociated by one or more alloimmune diseases, collagenous colitis,lymphocytic colitis, C. difficile colitis, and microscopic colitis.

In certain embodiments when the subject exhibits a digestive symptom,the digestive symptom appears from 2-14 (e.g., 2-3, 4-5, 6-7, 8-10, or11-14) days after the subject's exposure to coronavirus.

In certain embodiments, the method further comprises administering asecond therapeutic agent. As a non-limiting example of the foregoingembodiments, the second therapeutic agent is selected from the groupconsisting of azithromycin, remdesivir, hydroxychloroquine, colchicine,and chloroquine.

In certain embodiments, the niclosamide, or a pharmaceuticallyacceptable salt thereof, is administered by tablet or pill.

In certain embodiments, the method comprises orally administering theniclosamide, or a pharmaceutically acceptable salt thereof, as apharmaceutical composition, wherein the pharmaceutical composition iscapable of local delivery to the GI tract (e.g., lower GI tract).

In certain embodiments, the method comprises orally administering theniclosamide, or a pharmaceutically acceptable salt thereof, as apharmaceutical composition, wherein the pharmaceutical composition iscapable of local delivery to the colon.

In certain embodiments, the method comprises orally administering theniclosamide, or a pharmaceutically acceptable salt thereof, as apharmaceutical composition, wherein the pharmaceutical composition iscapable of local delivery to the small intestine.

In another aspect, the disclosure features a method of preventing (e.g.,reducing the risk of developing) COVID-19 in a subject (e.g., a human)at risk thereof, the method comprising administering an effective amountof niclosamide:

or a pharmaceutically acceptable salt thereof, to the subject (e.g., thehuman).

In certain of these embodiments, subject is selected from the groupconsisting of a healthcare worker, a resident of an assisted livingfacility or nursing home, a patient in a hospital for an unrelatedtreatment, and a person incarcerated or working in a prison or jailsetting. In certain embodiments, the subject is 60 years of age orolder. In certain embodiments, the subject suffers from one or morepreexisting medical conditions selected from the group consisting oflung disease, cardiovascular disease, cancer, colitis, hypertension, andan endocrine disease. In certain embodiments, the compound isadministered prior to exposure to the coronavirus or immediately afterexposure or presumed exposure to the coronavirus.

In another aspect, the disclosure features a method for clearingpersistent infection in an asymptomatic individual who may or may nothave previous COVID-19 illness caused by SARS-COV2, the methodcomprising administering an effective amount of niclosamide:

or a pharmaceutically acceptable salt thereof, to the subject.

In some embodiments, the methods described herein further comprise oneor more of the following: quarantine, self-quarantine, socialdistancing, frequent handwashing, and frequent environmentalsanitization.

In some embodiments of the methods described herein, the subject is ahuman.

In some embodiments, the methods described herein comprise administeringthe effective amount of the niclosamide compound, or a pharmaceuticallyacceptable salt thereof, to the respiratory system of the subject.

In certain embodiments, the methods described herein comprise locallyadministering an effective amount of the niclosamide compound, or apharmaceutically acceptable salt thereof, to the respiratory system ofthe subject.

In certain embodiments, the methods described herein comprise topicallyadministering an effective amount of the niclosamide compound, or apharmaceutically acceptable salt thereof, to the respiratory system ofthe subject.

In certain of the foregoing embodiments, the methods described hereincomprise locally and topically administering an effective amount of theniclosamide compound, or a pharmaceutically acceptable salt thereof, tothe respiratory system of the subject.

In some embodiments, the methods described herein comprise administeringthe effective amount of the niclosamide compound, or a pharmaceuticallyacceptable salt thereof, to the lungs of the subject.

In certain embodiments, the methods described herein comprise locallyadministering an effective amount of the niclosamide compound, or apharmaceutically acceptable salt thereof, to the lungs of the subject.

In certain embodiments, the methods described herein comprise topicallyadministering an effective amount of the niclosamide compound, or apharmaceutically acceptable salt thereof, to the lungs of the subject.

In certain embodiments, the methods described herein comprise locallyand topically administering an effective amount of the niclosamidecompound, or a pharmaceutically acceptable salt thereof, to the lungs ofthe subject.

In certain embodiments of the methods described herein, the niclosamidecompound, or a pharmaceutically acceptable salt thereof, is administeredby inhalation.

In another aspect, provided herein is a method for treating COVID-19 ina subject in need thereof, the method comprising administering aneffective amount of a niclosamide compound, or a pharmaceuticallyacceptable salt thereof, to the GI tract of the subject.

In certain embodiments, the method comprises locally administering aneffective amount of the niclosamide compound, or a pharmaceuticallyacceptable salt thereof to the GI tract of the subject.

In certain embodiments, the method comprises topically administering aneffective amount of the niclosamide compound, or a pharmaceuticallyacceptable salt thereof to the GI tract of the subject.

In certain of these embodiments, the niclosamide compound, or apharmaceutically acceptable salt thereof, is administered by rectaladministration. As a non-limiting example of the foregoing embodiments,the niclosamide compound, or a pharmaceutically acceptable salt thereof,is administered by enema, rectal gel, rectal foam, rectal aerosol, orsuppository. For example, the niclosamide compound, or apharmaceutically acceptable salt thereof, can be administered by enema.

In some embodiments, the method comprises orally administering theniclosamide compound, or a pharmaceutically acceptable salt thereof, asa pharmaceutical composition, wherein the pharmaceutical composition iscapable of local delivery to the digestive or GI tract. In certain ofthese embodiments, the pharmaceutical composition comprises one or morepharmaceutically acceptable excipients that chemically and/orstructurally predispose the composition for delivery of the niclosamidecompound, or a pharmaceutically acceptable salt thereof, to the lower GItract. For example, the composition comprises one or morepharmaceutically acceptable excipients that chemically and/orstructurally predispose the composition for delivery of the niclosamidecompound, or a pharmaceutically acceptable salt thereof, to the colon.As another non-limiting example, the composition comprises one or morepharmaceutically acceptable excipients that chemically and/orstructurally predispose the composition for delivery of the niclosamide,or a pharmaceutically acceptable salt thereof, to the ascending colonand/or transverse colon and/or distal colon. As another non-limitingexample, the composition comprises one or more pharmaceuticallyacceptable excipients that chemically and/or structurally predispose thecomposition for delivery of niclosamide, or a pharmaceuticallyacceptable salt thereof, to the small intestine (e.g., to the ileum).

The methods disclosed herein can further comprise a step of identifyinga subject having COVID-19. Identification of a subject as havingCOVID-19 can include the detection of RNA from severe acute respiratorysyndrome coronavirus 2 (SARS-CoV-2) in a biological sample from thesubject. In some embodiments, the biological sample is a respiratorysample. Non-limiting examples of respiratory samples that can be used todetect SARS-CoV-2 include a nasopharyngeal swab sample, an oropharyngealswab sample, a sputum sample, a bronchoalveolar lavage sample, anasopharyngeal aspirate, a nasopharyngeal wash, a nasal aspirate, anasal wash, and a lower respiratory tract aspirate. In some embodiments,the biological sample is a fecal sample and/or an anal/rectal swabsample. In some embodiments, polymerase chain reaction (PCR) is used todetect RNA from SARS-CoV-2 in a sample from a subject. Non-limitingexamples of types of PCR that can be used to identify a subject ashaving COVID-19 include reverse transcription PCR (RT-PCR), real-timePCR (e.g., quantitative PCR (qPCR)), and real-time RT-PCR (rRT-PCR). Insome embodiments, a specific gene from SARS-CoV-2 is detected. Forexample, the E gene, RNA-dependent RNA polymerase gene (RdRp) gene,ORF1a gene, ORF1b gene, N gene, or a combination thereof can be detectedusing primers or probes specific to the gene or a portion thereof. Insome embodiments, detection of RNA from SARS-CoV-2 can include using akit comprising, for example, PCR reagents and primers and/or probes fordetecting RNA from SARS-CoV-2 (e.g., primers and/or probes specific tothe E gene, RNA-dependent RNA polymerase gene (RdRp) gene, ORF1a gene,ORF1b gene, N gene, or a combination thereof). Many commercial kits areavailable to detect RNA from SARS-CoV-2. Non-limiting examples of suchkits include PowerChek™ 2019-nCov RT-PCR kit (Kogene Biotech), RT-PCRAllplex 2019-nCoV Assay (Seegene); STANDARD M n-CoV Real-Time DetectionKit (SD Biosensor); rRT-PCR XPERT® Xpress SARS-CoV-2 (CepheidInnovation); and Primerdesign Ltd COVID-19 GENESIG® Real-Time PCR assay.See also, the kits approved by the Food and Drug Administration(fda.gov/medical-devices/emergency-situations-medical-devices/emergency-use-authorizations#covid19ivd).

In some embodiments, the E gene and RdRp gene specific to SARS-CoV-2 isdetected (see, e.g., PowerChek™ 2019-nCov RT-PCR kit; RT-PCR Allplex2019-nCoV Assay; and STANDARD M n-CoV Real-Time Detection Kit (SDBiosensor)). In some embodiments, the ORF1a gene and N gene are detected(see, e.g., DiaPlexQ™ Novel Coronavirus Detection Kit (2019-nCoV)(SolGent Co., Ltd.)) In some embodiments, the RdRP gene, E gene, and Ngene are detected (see, e.g., Corman et al. Eurosurveillance, 25,2000045 (2020)). In some embodiments, the ORF1 ab genome region isdetected (see, e.g., Primerdesign Ltd COVID-19 GENESIG® Real-Time PCRassay). In some embodiments, the N2 gene and E gene are detected (see,e.g., rRT-PCR XPERT® Xpress SARS-CoV-2 (Cepheid Innovation)). In someembodiments, primers and probes to detect the RdRp gene spanningnucleotides 12621-12727 and 14010-14116 (positions according SARS-CoV,NC_004718) can be used to detect SARS-CoV-2. See, e.g. the World HealthOrganization Protocol from the National Reference Center for RespiratoryViruses, Institut Pasteur, Paris(www.who.int/docs/default-source/coronaviruse/real-time-rt-pcr-assays-for-the-detection-of-sars-cov-2-institut-pasteur-paris.pdf?sfvrsn=3662fcb6_2).In some embodiments, a first gene is detected in a screening test and asecond gene is detected for confirmation. For example, the N gene fromSARS-CoV-2 can be detected in a screening assay and ORF1b fromSARS-CoV-2 can be detected as a confirmatory assay.

In some embodiments, rRT-PCR can be used to monitor a subject withCOVID-19. For example, prior to starting a therapy as described herein(e.g., a niclosamide compound, or a pharmaceutically acceptable saltthereof as described herein), a biological sample can be obtained fromthe subject and the level of SARS-CoV-2 RNA (e.g., the level of RNAcorresponding to an SARS-CoV-2 gene described herein) determined in thebiological sample. This sample can be considered a base-line sample. Thesubject can then be administered one or more doses of a therapy asdescribed herein (e.g., a niclosamide compound, or a pharmaceuticallyacceptable salt thereof as described herein) and the levels ofSARS-CoV-2 RNA can be monitored (e.g., after the first dose, seconddose, third dose, etc. or after one week, two weeks, three weeks, fourweeks, etc.). If the level of SARS-CoV-2 RNA is lower than the baselinesample (e.g., a 1% to about a 99% reduction, a 1% to about a 95%reduction, a 1% to about a 90% reduction, a 1% to about a 85% reduction,a 1% to about a 80% reduction, a 1% to about a 75% reduction, a 1%reduction to about a 70% reduction, a 1% reduction to about a 65%reduction, a 1% reduction to about a 60% reduction, a 1% reduction toabout a 55% reduction, a 1% reduction to about a 50% reduction, a 1%reduction to about a 45% reduction, a 1% reduction to about a 40%reduction, a 1% reduction to about a 35% reduction, a 1% reduction toabout a 30% reduction, a 1% reduction to about a 25% reduction, a 1%reduction to about a 20% reduction, a 1% reduction to about a 15%reduction, a 1% reduction to about a 10% reduction, a 1% to about a 5%reduction, about a 5% to about a 99% reduction, about a 10% to about a99% reduction, about a 15% to about a 99% reduction, about a 20% toabout a 99% reduction, about a 25% to about a 99% reduction, about a 30%to about a 99% reduction, about a 35% to about a 99% reduction, about a40% to about a 99% reduction, about a 45% to about a 99% reduction,about a 50% to about a 99% reduction, about a 55% to about a 99%reduction, about a 60% to about a 99% reduction, about a 65% to about a99% reduction, about a 70% to about a 99% reduction, about a 75% toabout a 95% reduction, about a 80% to about a 99% reduction, about a 90%reduction to about a 99% reduction, about a 95% to about a 99%reduction, about a 5% to about a 10% reduction, about a 5% to about a25% reduction, about a 10% to about a 30% reduction, about a 20% toabout a 40% reduction, about a 25% to about a 50% reduction, about a 35%to about a 55% reduction, about a 40% to about a 60% reduction, about a50% reduction to about a 75% reduction, about a 60% reduction to about80% reduction, or about a 65% to about a 85% reduction etc.), this isindicative of responsiveness to therapy. In some embodiments, the levelof SARS-CoV-2 RNA in a biological sample obtained from the subject (n)is compared to the sample taken just previous (n−1). If the level ofSARS-CoV-2 RNA in the n sample is lower than the n−1 sample (e.g., a 1%to about a 99% reduction, a 1% to about a 95% reduction, a 1% to about a90% reduction, a 1% to about a 85% reduction, a 1% to about a 80%reduction, a 1% to about a 75% reduction, a 1% reduction to about a 70%reduction, a 1% reduction to about a 65% reduction, a 1% reduction toabout a 60% reduction, a 1% reduction to about a 55% reduction, a 1%reduction to about a 50% reduction, a 1% reduction to about a 45%reduction, a 1% reduction to about a 40% reduction, a 1% reduction toabout a 35% reduction, a 1% reduction to about a 30% reduction, a 1%reduction to about a 25% reduction, a 1% reduction to about a 20%reduction, a 1% reduction to about a 15% reduction, a 1% reduction toabout a 10% reduction, a 1% to about a 5% reduction, about a 5% to abouta 99% reduction, about a 10% to about a 99% reduction, about a 15% toabout a 99% reduction, about a 20% to about a 99% reduction, about a 25%to about a 99% reduction, about a 30% to about a 99% reduction, about a35% to about a 99% reduction, about a 40% to about a 99% reduction,about a 45% to about a 99% reduction, about a 50% to about a 99%reduction, about a 55% to about a 99% reduction, about a 60% to about a99% reduction, about a 65% to about a 99% reduction, about a 70% toabout a 99% reduction, about a 75% to about a 95% reduction, about a 80%to about a 99% reduction, about a 90% reduction to about a 99%reduction, about a 95% to about a 99% reduction, about a 5% to about a10% reduction, about a 5% to about a 25% reduction, about a 10% to abouta 30% reduction, about a 20% to about a 40% reduction, about a 25% toabout a 50% reduction, about a 35% to about a 55% reduction, about a 40%to about a 60% reduction, about a 50% reduction to about a 75%reduction, about a 60% reduction to about 80% reduction, or about a 65%to about a 85% reduction, etc.), this is indicative of responsiveness totherapy. In the case of responsiveness to therapy, the subject can to beadministered one or more doses of therapy (e.g., a niclosamide compound,or a pharmaceutically acceptable salt thereof) and the SARS-CoV-2 RNAcan be continued to be monitored.

In some embodiments, COVID-19 can be severe or mild. See, e.g, Liu etal. Lancet Infect. Dis. 2020; doi.org/10.1016/S1473-3099(20)30232-2.Also provided herein are methods for treating mild COVID-19 in a subjectin need thereof, the method comprising administering an effective amountof a niclosamide compound, or a pharmaceutically acceptable saltthereof, to the subject. In some embodiments, a subject having mildCOVID-19 has: (i) a respiratory rate of <30 breaths per min; (ii) anoxygen saturation at rest of >93%; and (iii) a ratio of partial pressureof arterial oxygen to fractional concentration of oxygen inspired airof >300 mm Hg. In some embodiments, a subject having mild COVID-19 doesnot have a severe disease complication. Severe disease complications caninclude, but are not limited to, respiratory failure, requirement ofmechanical ventilation, septic shock, and non-respiratory organ failure.In some embodiments, a subject having mild COVID-19 does not havedigestive symptoms. For example, the subject does not have diarrhea,abdominal pain, or vomiting. In some embodiments, a subject having mildCOVID-19 has a low viral load. Viral load can be estimated using the ΔCtmethod (Ct_(sample)−Ct_(ref)). In some embodiments, a sample from asubject with a low viral load has a ΔCt>3. For example, a sample from asubject with a low viral load can have a ΔCt of about 3 to about 15. Insome embodiments, the niclosamide compound, or a pharmaceuticallyacceptable salt thereof, is administered in combination with one or moreadditional therapeutic agents (e.g., any of the additional therapeuticagents described herein).

Also provided herein are methods for treating severe COVID-19 in asubject in need thereof, the method comprising administering aneffective amount of a niclosamide compound, or a pharmaceuticallyacceptable salt thereof, to the subject. In some embodiments, a subjecthaving severe COVID-19 has at least one of: (i) respiratory distress(i.e., ≥30 breaths per min); (ii) an oxygen saturation at rest of ≤93%;(iii) a ratio of partial pressure of arterial oxygen to fractionalconcentration of oxygen inspired air of ≤300 mm Hg; and (iv) a severedisease complication, e.g., a severe disease complication as describedherein. In some embodiments, a subject having severe COVID-19 has one ormore digestive symptoms. For example, the subject has one or more ofdiarrhea, abdominal pain, and vomiting. In some embodiments, a subjecthaving severe COVID-19 has one or more of an elevated liver enzymelevel, lower monocyte count, and longer prothrombin time. For example,an elevated liver enzyme level can include an AST or ALT level of >50U/L. In some embodiments, a subject having severe COVID-19 has a highviral load. In some embodiments, a sample from a subject with a highviral load has a ΔCt≤2. For example, a sample from a subject with a lowviral load can have a ΔCt of about 2 to about −10. In some embodiments,the niclosamide compound, or a pharmaceutically acceptable salt thereof,is administered in combination with one or more additional therapeuticagents (e.g., any of the additional therapeutic agents describedherein). Also provided herein are methods for treating mild COVID-19 ina subject in need thereof, the method comprising administering aneffective amount of a niclosamide compound, or a pharmaceuticallyacceptable salt thereof, to the nasal cavity of the subject. In someembodiments, a subject having mild COVID-19 has: (i) a respiratory rateof ≤30 breaths per min; (ii) an oxygen saturation at rest of ≥93%; and(iii) a ratio of partial pressure of arterial oxygen to fractionalconcentration of oxygen inspired air of ≥300 mm Hg. In some embodiments,the subject does not have a severe disease complication. In someembodiments, the subject having mild COVID-19 has a low viral load(e.g., a ΔCt of about 3 to about 15). In some embodiments, theniclosamide compound, or a pharmaceutically acceptable salt thereof, isformulated as an intranasal spray, ointment, or gel (e.g., any of theintranasal compositions described herein).

Also provided herein are methods of treating a subject having COVID-19that include: identifying a subject that has: (i) a respiratory rate of<30 breaths per min; (ii) an oxygen saturation at rest of >93%; and(iii) a ratio of partial pressure of arterial oxygen to fractionalconcentration of oxygen inspired air of >300 mm Hg; and administering tothe nasal cavity of the identified subject a treatment that includes aniclosamide compound, or a pharmaceutically acceptable salt thereof. Insome embodiments, the subject does not have a severe diseasecomplication. In some embodiments, the subject has a low viral load(e.g., a ΔCt of about 3 to about 15). In some embodiments, theniclosamide compound, or a pharmaceutically acceptable salt thereof, isformulated as an intranasal spray, ointment, or gel (e.g., any of theintranasal compositions described herein).

Also provided herein are methods for treating severe COVID-19 in asubject in need thereof, the method comprising administering aneffective amount of a niclosamide compound, or a pharmaceuticallyacceptable salt thereof, to the lungs of the subject. In someembodiments, a subject having severe COVID-19 has at least one of: (i)respiratory distress (i.e., ≥30 breaths per min); (ii) an oxygensaturation at rest of ≤93%; (iii) a ratio of partial pressure ofarterial oxygen to fractional concentration of oxygen inspired air of≤300 mm Hg; and (iv) a severe disease complication, e.g., a severedisease complication as described herein. In some embodiments, thesubject has one or more digestive symptoms (e.g., any of the digestivesymptoms described herein). In some embodiments, the subject has one ormore of an elevated liver enzyme level, lower monocyte count, and alonger prothrombin time. In some embodiments, the subject has a highviral load (e.g., a ΔCt of about 2 to about −10). In some embodiments,the niclosamide compound, or a pharmaceutically acceptable salt thereof,is formulated for delivery by inhalation (e.g., any of the compositionsfor inhalation described herein).

Also provided herein are methods of treating a subject having COVID-19that include: identifying a subject that has at least one of (i)respiratory distress (i.e., ≥30 breaths per min); (ii) an oxygensaturation at rest of ≤93%; (iii) a ratio of partial pressure ofarterial oxygen to fractional concentration of oxygen inspired air of≤300 mm Hg; and (iv) a severe disease complication, e.g., a severedisease complication as described herein; and administering to the lungsof the identified subject a treatment that includes a niclosamidecompound, or a pharmaceutically acceptable salt thereof. In someembodiments, the subject has one or more digestive symptoms (e.g., anyof the digestive symptoms described herein). In some embodiments, thesubject has one or more of an elevated liver enzyme level, lowermonocyte count, and a longer prothrombin time. In some embodiments, thesubject has a high viral load (e.g., a ΔCt of about 2 to about −10). Insome embodiments, the niclosamide compound, or a pharmaceuticallyacceptable salt thereof, is formulated for delivery by inhalation (e.g.,any of the compositions for inhalation described herein).

Also provided herein are methods for treating severe COVID-19 in asubject in need thereof, the method comprising administering aneffective amount of a niclosamide compound, or a pharmaceuticallyacceptable salt thereof, to the GI tract of the subject. In someembodiments, a subject having severe COVID-19 has at least one of: (i)respiratory distress (i.e., ≥30 breaths per min); (ii) an oxygensaturation at rest of ≤93%; (iii) a ratio of partial pressure ofarterial oxygen to fractional concentration of oxygen inspired air of≤300 mm Hg; and (iv) a severe disease complication, e.g., a severedisease complication as described herein. In some embodiments, thesubject has one or more digestive symptoms (e.g., any of the digestivesymptoms described herein). In some embodiments, the subject has one ormore of an elevated liver enzyme level, lower monocyte count, and alonger prothrombin time. In some embodiments, the subject has a highviral load (e.g., a ΔCt of about 2 to about −10). In some embodiments,the niclosamide compound, or a pharmaceutically acceptable salt thereof,is formulated for oral delivery.

Also provided herein are methods of treating a subject having COVID-19that include: (a) identifying a subject having (i) a respiratory rate of<30 breaths per min; (ii) an oxygen saturation at rest of >93%; and(iii) a ratio of partial pressure of arterial oxygen to fractionalconcentration of oxygen inspired air of >300 mm Hg; and (b)administering one or more doses of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the nasal cavity of thesubject; (c) after (a) and (b), identifying whether the subject has atleast one of: (i) respiratory distress (i.e., ≥30 breaths per min); (ii)an oxygen saturation at rest of ≤93%; (iii) a ratio of partial pressureof arterial oxygen to fractional concentration of oxygen inspired air of≤300 mm Hg; and (iv) a severe disease complication, e.g., a severedisease complication as described herein; and (d) administering one ormore doses of a niclosamide compound, or a pharmaceutically acceptablesalt thereof, to the lungs of the subject in which the subject has atleast one of: (i) respiratory distress (i.e., ≥30 breaths per min); (ii)an oxygen saturation at rest of ≤93%; (iii) a ratio of partial pressureof arterial oxygen to fractional concentration of oxygen inspired air of≤300 mm Hg; and (iv) a severe disease complication, e.g., a severedisease complication as described herein; or (e) administeringadditional doses of the niclosamide compound, or a pharmaceuticallyacceptable salt thereof, to the nasal cavity of the subject in which (i)a respiratory rate of <30 breaths per min; (ii) an oxygen saturation atrest of >93%; and (iii) a ratio of partial pressure of arterial oxygento fractional concentration of oxygen inspired air of >300 mm Hg. Insome embodiments, the subject identified in step (a) does not have asevere disease complication. In some embodiments, wherein theniclosamide compound, or a pharmaceutically acceptable salt thereof isadministered to the nasal cavity of the subject, the niclosamidecompound, or the pharmaceutically acceptable salt thereof, is formulatedas an intranasal spray, ointment, or gel (e.g., any of the intranasalcompositions described herein). In some embodiments, wherein theniclosamide compound, or a pharmaceutically acceptable salt thereof isadministered to the lungs of the subject, the niclosamide compound, orthe pharmaceutically acceptable salt thereof, is formulated for deliveryby inhalation (e.g., any of the compositions for inhalation describedherein).

Also provided herein are methods of treating a subject having COVID-19that include: (a) identifying a subject having (i) a respiratory rate of<30 breaths per min; (ii) an oxygen saturation at rest of >93%; and(iii) a ratio of partial pressure of arterial oxygen to fractionalconcentration of oxygen inspired air of >300 mm Hg; and (b)administering one or more doses of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the nasal cavity of thesubject; (c) after (a) and (b), identifying whether the subject has atleast one of: (i) respiratory distress (i.e., ≥30 breaths per min); (ii)an oxygen saturation at rest of ≤93%; (iii) a ratio of partial pressureof arterial oxygen to fractional concentration of oxygen inspired air of≤300 mm Hg; and (iv) a severe disease complication, e.g., a severedisease complication as described herein; and (d) administering one ormore doses of a niclosamide compound, or a pharmaceutically acceptablesalt thereof, to the GI tract of the subject in which the subject has atleast one of: (i) respiratory distress (i.e., ≥30 breaths per min); (ii)an oxygen saturation at rest of ≤93%; (iii) a ratio of partial pressureof arterial oxygen to fractional concentration of oxygen inspired air of≤300 mm Hg; and (iv) a severe disease complication, e.g., a severedisease complication as described herein; or (e) administeringadditional doses of the niclosamide compound, or a pharmaceuticallyacceptable salt thereof, to the nasal cavity of the subject in which (i)a respiratory rate of <30 breaths per min; (ii) an oxygen saturation atrest of >93%; and (iii) a ratio of partial pressure of arterial oxygento fractional concentration of oxygen inspired air of >300 mm Hg. Insome embodiments, the subject identified in step (a) does not have asevere disease complication. In some embodiments, wherein theniclosamide compound, or a pharmaceutically acceptable salt thereof isadministered to the nasal cavity of the subject, the niclosamidecompound, or the pharmaceutically acceptable salt thereof, is formulatedas an intranasal spray, ointment, or gel (e.g., any of the intranasalcompositions described herein). In some embodiments, wherein theniclosamide compound, or a pharmaceutically acceptable salt thereof isadministered to the GI tract of the subject, the niclosamide compound,or the pharmaceutically acceptable salt thereof, is formulated as anoral composition (e.g., any of the oral compositions described herein).

Also provided herein are methods of treating a subject having COVID-19that include: (a) identifying a subject having (i) a respiratory rate of<30 breaths per min; (ii) an oxygen saturation at rest of >93%; and(iii) a ratio of partial pressure of arterial oxygen to fractionalconcentration of oxygen inspired air of >300 mm Hg; and (b)administering one or more doses of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the nasal cavity of thesubject; (c) after (a) and (b), identifying whether the subject has atleast one of: (i) respiratory distress (i.e., ≥30 breaths per min); (ii)an oxygen saturation at rest of ≤93%; (iii) a ratio of partial pressureof arterial oxygen to fractional concentration of oxygen inspired air of≤300 mm Hg; and (iv) a severe disease complication; and (d)administering one or more doses of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the GI tract of the subjectand administering one or more doses of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the lungs of the subject inwhich the subject has at least one of: (i) respiratory distress (i.e.,≥30 breaths per min); (ii) an oxygen saturation at rest of ≤93%; (iii) aratio of partial pressure of arterial oxygen to fractional concentrationof oxygen inspired air of ≤300 mm Hg; and (iv) a severe diseasecomplication, e.g., a severe disease complication as described herein;or (e) administering additional doses of the niclosamide compound, or apharmaceutically acceptable salt thereof, to the nasal cavity of thesubject in which (i) a respiratory rate of <30 breaths per min; (ii) anoxygen saturation at rest of >93%; and (iii) a ratio of partial pressureof arterial oxygen to fractional concentration of oxygen inspired airof >300 mm Hg. In some embodiments, the subject identified in step (a)does not have a severe disease complication. In some embodiments,wherein the niclosamide compound, or a pharmaceutically acceptable saltthereof is administered to the nasal cavity of the subject, theniclosamide compound, or the pharmaceutically acceptable salt thereof,is formulated as an intranasal spray, ointment, or gel (e.g., any of theintranasal compositions described herein). In some embodiments, whereinthe niclosamide compound, or a pharmaceutically acceptable salt thereofis administered to the GI tract of the subject, the niclosamidecompound, or the pharmaceutically acceptable salt thereof, is formulatedas an oral composition (e.g., any of the oral compositions describedherein). In some embodiments, wherein the niclosamide compound, or apharmaceutically acceptable salt thereof is administered to the lungs ofthe subject, the niclosamide compound, or the pharmaceuticallyacceptable salt thereof, is formulated for delivery by inhalation (e.g.,any of the compositions for inhalation described herein).

Also provided herein are methods of treating a subject having COVID-19that include: (a) identifying a subject having at least one of (i)respiratory distress (i.e., ≥30 breaths per min); (ii) an oxygensaturation at rest of ≤93%; (iii) a ratio of partial pressure ofarterial oxygen to fractional concentration of oxygen inspired air of≤300 mm Hg; and (iv) a severe disease complication; and (b)administering one or more doses of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the lungs of the subject;(c) after (a) and (b), identifying whether the subject has (i) arespiratory rate of <30 breaths per min; (ii) an oxygen saturation atrest of >93%; and (iii) a ratio of partial pressure of arterial oxygento fractional concentration of oxygen inspired air of >300 mm Hg; and(d) administering one or more doses of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the nasal cavity of thesubject in which the subject has (i) a respiratory rate of <30 breathsper min; (ii) an oxygen saturation at rest of >93%; and (iii) a ratio ofpartial pressure of arterial oxygen to fractional concentration ofoxygen inspired air of >300 mm Hg; or (e) administering additional dosesof the niclosamide compound, or a pharmaceutically acceptable saltthereof, to the lungs of the subject in which the subject has at leastone of (i) respiratory distress (i.e., ≥30 breaths per min); (ii) anoxygen saturation at rest of ≤93%; (iii) a ratio of partial pressure ofarterial oxygen to fractional concentration of oxygen inspired air of≤300 mm Hg; and (iv) a severe disease complication, e.g., a severedisease complication as described herein. In some embodiments, thesubject identified in step (c) does not have a severe diseasecomplication. In some embodiments, wherein the niclosamide compound, ora pharmaceutically acceptable salt thereof is administered to the GItract of the subject, the niclosamide compound, or the pharmaceuticallyacceptable salt thereof, is formulated as an oral composition (e.g., anyof the oral compositions described herein). In some embodiments, whereinthe niclosamide compound, or a pharmaceutically acceptable salt thereofis administered to the lungs of the subject, the niclosamide compound,or the pharmaceutically acceptable salt thereof, is formulated fordelivery by inhalation (e.g., any of the compositions for inhalationdescribed herein). Also provided herein are methods of treating asubject having COVID-19 that include: (a) identifying a subject having alow viral load (e.g., a ΔCt of about 3 to about 15); and (b)administering one or more doses of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the nasal cavity of thesubject; (c) after (a) and (b), identifying whether the subject has ahigh viral load (e.g., a ΔCt of about 2 to about −10); and (d)administering one or more doses of a niclosamide compound, or apharmaceutically acceptable salt thereof, to the lungs of the subject inwhich the subject has a high viral load (e.g., a ΔCt of about 2 to about−10); or (e) administering additional doses of the niclosamide compound,or a pharmaceutically acceptable salt thereof, to the nasal cavity ofthe subject in which the subject has a low viral load (e.g., a ΔCt ofabout 3 to about 15). In some embodiments, the subject identified instep (a) does not have a severe disease complication. In someembodiments, wherein the niclosamide compound, or a pharmaceuticallyacceptable salt thereof is administered to the nasal cavity of thesubject, the niclosamide compound, or the pharmaceutically acceptablesalt thereof, is formulated as an intranasal spray, ointment, or gel(e.g., any of the intranasal compositions described herein). In someembodiments, wherein the niclosamide compound, or a pharmaceuticallyacceptable salt thereof is administered to the lungs of the subject, theniclosamide compound, or the pharmaceutically acceptable salt thereof,is formulated for delivery by inhalation (e.g., any of the compositionsfor inhalation described herein).

Also provided herein are methods of treating a subject having COVID-19that include: (a) identifying a subject having a low viral load (e.g., aΔCt of about 3 to about 15); and (b) administering one or more doses ofa niclosamide compound, or a pharmaceutically acceptable salt thereof,to the nasal cavity of the subject; (c) after (a) and (b), identifyingwhether the subject has a high viral load (e.g., a ΔCt of about 2 toabout −10); and (d) administering one or more doses of a niclosamidecompound, or a pharmaceutically acceptable salt thereof, to the GI tractof the subject in which the subject has a high viral load (e.g., a ΔCtof about 2 to about −10); or (e) administering additional doses of theniclosamide compound, or a pharmaceutically acceptable salt thereof, tothe nasal cavity of the subject in which the subject has a low viralload (e.g., a ΔCt of about 3 to about 15). In some embodiments, thesubject identified in step (a) does not have a severe diseasecomplication. In some embodiments, wherein the niclosamide compound, ora pharmaceutically acceptable salt thereof is administered to the nasalcavity of the subject, the niclosamide compound, or the pharmaceuticallyacceptable salt thereof, is formulated as an intranasal spray, ointment,or gel (e.g., any of the intranasal compositions described herein). Insome embodiments, wherein the niclosamide compound, or apharmaceutically acceptable salt thereof is administered to the GI tractof the subject, the niclosamide compound, or the pharmaceuticallyacceptable salt thereof, is formulated as an oral composition (e.g., anyof the oral compositions described herein).

Also provided herein are methods of treating a subject having COVID-19that include: (a) identifying a subject having a low viral load (e.g., aΔCt of about 3 to about 15); and (b) administering one or more doses ofa niclosamide compound, or a pharmaceutically acceptable salt thereof,to the nasal cavity of the subject; (c) after (a) and (b), identifyingwhether the subject has a high viral load (e.g., a ΔCt of about 2 toabout −10); and (d) administering one or more doses of a niclosamidecompound, or a pharmaceutically acceptable salt thereof, to the GI tractof the subject and administering one or more doses of a niclosamidecompound, or a pharmaceutically acceptable salt thereof, to the lungs ofthe subject in which the subject has a high viral load (e.g., a ΔCt ofabout 2 to about −10); or (e) administering additional doses of theniclosamide compound, or a pharmaceutically acceptable salt thereof, tothe nasal cavity of the subject in which the subject has a low viralload (e.g., a ΔCt of about 3 to about 15). In some embodiments, thesubject identified in step (a) does not have a severe diseasecomplication. In some embodiments, wherein the niclosamide compound, ora pharmaceutically acceptable salt thereof is administered to the nasalcavity of the subject, the niclosamide compound, or the pharmaceuticallyacceptable salt thereof, is formulated as an intranasal spray, ointment,or gel (e.g., any of the intranasal compositions described herein). Insome embodiments, wherein the niclosamide compound, or apharmaceutically acceptable salt thereof is administered to the GI tractof the subject, the niclosamide compound, or the pharmaceuticallyacceptable salt thereof, is formulated as an oral composition (e.g., anyof the oral compositions described herein). In some embodiments, whereinthe niclosamide compound, or a pharmaceutically acceptable salt thereofis administered to the lungs of the subject, the niclosamide compound,or the pharmaceutically acceptable salt thereof, is formulated fordelivery by inhalation (e.g., any of the compositions for inhalationdescribed herein).

Also provided herein are methods of treating a subject having COVID-19that include: (a) identifying a subject having 19 has a high viral load(e.g., a ΔCt of about 2 to about −10); and (b) administering one or moredoses of a niclosamide compound, or a pharmaceutically acceptable saltthereof, to the lungs of the subject; (c) after (a) and (b), identifyingwhether the subject has a low viral load (e.g., a ΔCt of about 3 toabout 15); and (d) administering one or more doses of a niclosamidecompound, or a pharmaceutically acceptable salt thereof, to the nasalcavity of the subject in which the subject has a low viral load (e.g., aΔCt of about 3 to about 15); or (e) administering additional doses ofthe niclosamide compound, or a pharmaceutically acceptable salt thereof,to the lungs of the subject in which the subject has a high viral load(e.g., a ΔCt of about 2 to about −10). In some embodiments, the subjectidentified in step (c) does not have a severe disease complication. Insome embodiments, wherein the niclosamide compound, or apharmaceutically acceptable salt thereof is administered to the GI tractof the subject, the niclosamide compound, or the pharmaceuticallyacceptable salt thereof, is formulated as an oral composition (e.g., anyof the oral compositions described herein). In some embodiments, whereinthe niclosamide compound, or a pharmaceutically acceptable salt thereofis administered to the lungs of the subject, the niclosamide compound,or the pharmaceutically acceptable salt thereof, is formulated fordelivery by inhalation (e.g., any of the compositions for inhalationdescribed herein).

Combination Therapy

In some embodiments, the methods and compositions described herein aresuitable for use in combination therapy with various other therapeuticregimens. In certain embodiments, the niclosamide compounds, orpharmaceutically acceptable salts thereof, and methods described hereincan be used to treat side effects produced by such therapeutic regimens.

In some embodiments, the methods and compositions described herein aresuitable for use in combination therapy with one or more additionaltherapeutic agents.

In certain embodiments, the one or more additional therapeutic agents isadministered to the subject prior to contacting with or administeringthe niclosamide compound, or a pharmaceutically acceptable salt thereof,(e.g., about one hour prior, or about 6 hours prior, or about 12 hoursprior, or about 24 hours prior, or about 48 hours prior, or about 1 weekprior, or about 1 month prior).

In other embodiments, the one or more additional therapeutic agents isadministered to the subject at about the same time as contacting with oradministering the niclosamide compound, or a pharmaceutically acceptablesalt thereof. By way of example, the second therapeutic agent or regimenand the niclosamide compound, or a pharmaceutically acceptable saltthereof, are provided to the subject simultaneously in the same dosageform. As another example, the second therapeutic agent or regimen andthe niclosamide compound, or a pharmaceutically acceptable salt thereof,are provided to the subject concurrently in separate dosage forms.

In still other embodiments, the one or more additional therapeuticagents is administered to the subject after contacting with oradministering the niclosamide compound, or a pharmaceutically acceptablesalt thereof, (e.g., about one hour after, or about 6 hours after, orabout 12 hours after, or about 24 hours after, or about 48 hours after,or about 1 week after, or about 1 month after).

In some embodiments, one or more therapies can be used in combinationwith the materials and/or methods described herein. In some embodiments,a combination therapy can include one or more of a macrolide antibiotic,an anti-malarial agent, an anti-diabetic agent, an angiotensin receptorinhibitor, an angiotensin-converting enzyme (ACE) inhibitor, a statin, apolymerase inhibitor (e.g., a RNA-dependent RNA polymerase inhibitor), aprotease inhibitor, a neuraminidase inhibitor, a fusion inhibitor, atransmembrane protease serine 2 (TMPRSS2) inhibitor, a broad-spectrumantiviral agent, a JAK-STAT pathway inhibitor, a DNA synthesisinhibitor, a phosphodiesterase 5 (PDE5) inhibitor, a monoclonalantibody, passive antibody therapy, recombinant humanangiotensin-converting enzyme 2 (rhACE2), traditional Chinese medicine,a pharmaceutically acceptable salt or solvate of any thereof, or two ormore of any thereof. In some embodiments, the macrolide antibioticand/or anti-malarial agent is a lysosomotropic agent. Non-limitingexamples of lysosomotropic agents include azithromycin,hydroxychloroquine, chloroquine, and ammonium chloride. Non-limitingexamples of an anti-diabetic agent include a biguanide, a sulfonylurea,a glitazar, a thiazolidinedione, a dipeptidyl peptidase 4 (DPP-4)inhibitor, a meglitinide, a sodium-glucose linked transporter 2 (SGLT2)inhibitor, a glitazone, a GRP40 agonist, a glucose-dependentinsulinotropic peptide (GIP), an insulin or insulin analogue, an alphaglucosidase inhibitor, a sodium-glucose linked transporter 1 (SGLT1)inhibitor. In some embodiments, the biguanide is metformin. Anon-limiting example of an angiotensin receptor inhibitor includes asartan (e.g., eprosartan, olmesartan, olmesartan medoxomil, valsartan,candesartan, candesartan cilexetil, losartan, telmisartan, irbesartan,BRA-657, and azilsartan medoxomil). Non-limiting examples of an ACEinhibitor include: quinapril, fosinopril perindopril, captopril,enalapril, enalaprilat, ramipril, cilazapril, delapril, fosenopril,zofenopril, indolapril, benazepril, lisinopril, spirapril, trandolapril,perindep, pentopril, moexipril, rescinnamine, and pivopril. Non-limitingexamples of a statin include atorvastatin, fluvastatin, lovastatin,pitavastatin, pravastatin, rosuvastatin, and simvastatin, cerivastatin,and mevastatin. Non-limiting examples of polymerase inhibitors includeganciclovir, valganciclovir, and RNA-dependent RNA polymerase (RdRP)inhibitors (e.g., remdesivir, ribavirin, and favipiravir). Non-limitingexamples of protease inhibitors include lopinavir, ritonavir, indinavir,atazanavir, nelfinavir, darunavir, tipranavir, amprenavir, andfosamprenavir. A non-limiting example of a neuraminidase inhibitor isoseltamivir. A non-limiting example of a fusion inhibitor is umifenovir.A non-limiting example of a TMPRSS2 inhibitor is camostat. Non-limitingexamples of broad-spectrum antiviral agents include nitazoxanide,chloroquine, hydroxychloroquine, and interferon (e.g., interferon alfa).Non-limiting examples of JAK-STAT pathway inhibitors includebaricitinib, fedratinib, and ruxolitinib. Non-limiting examples of DNAsynthesis inhibitors include tenofovir disoproxil and lamivudine. Anon-limiting example of a PDE5 inhibitor is sildenafil. A non-limitingexample of traditional Chinese medicine is huaier extract. See, e.g.,Liu, Cynthia, et al. “Research and Development on Therapeutic Agents andVaccines for COVID-19 and Related Human Coronavirus Diseases.” (2020).doi/10.1021/acscentsci.0c00272; Lai, Chih-Cheng, et al. “Severe acuterespiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirusdisease-2019 (COVID-19): the epidemic and the challenges.” Internationaljournal of antimicrobial agents (2020): 105924; Chang, Yu-Chuan, et al.“Potential therapeutic agents for COVID-19 based on the analysis ofprotease and RNA polymerase docking.” (2020). doi:10.20944/preprint5202002.0242.v1; NCT04252885; NCT04306497; NCT04287686;NCT04307693; NCT04292899; NCT04304313; NCT04291053; Ko W C, Rolain J M,Lee N Y, et al. Arguments in favor of remdesivir for treating SARS-CoV-2infections [published online ahead of print, 2020 Mar. 5]. Int JAntimicrob Agents. 2020; 105933. doi:10.1016/j.ijantimicag.2020.105933;Dhama, K., et al. (2020). Coronavirus Disease 2019—COVID-19. doi:10.20944/preprints202003.0001.v1; Stebbing, Justin, et al. “COVID-19:combining antiviral and anti-inflammatory treatments.” The LancetInfectious Diseases (2020); Yang, Naidi, and Han-Ming Shen. “Targetingthe Endocytic Pathway and Autophagy Process as a Novel TherapeuticStrategy in COVID-19.” Int J Biol Sci 16.10 (2020): 1724-1731;Casadevall, Arturo, and Liise-anne Pirofski. “The convalescent seraoption for containing COVID-19.” The Journal of Clinical Investigation130.4 (2020); Shanmugaraj, Balamurugan, et al. “Perspectives onmonoclonal antibody therapy as potential therapeutic intervention forCoronavirus disease-19 (COVID-19).” Asian Pacific journal of allergy andimmunology (2020); and Xu, Jimin, et al. “Broad Spectrum Antiviral AgentNiclosamide and Its Therapeutic Potential.” ACS Infectious Diseases(2020), each of which is incorporated by reference herein in itsentirety.

Provided herein are methods for treating COVID-19 in a subject in needthereof, the method comprising administering a niclosamide compound, ora pharmaceutically acceptable salt thereof, and a lysosomotropic agentto the subject. In some embodiments, the lysosomotropic agent isselected from azithromycin, hydroxychloroquine, chloroquine, ammoniumchloride, and a combination thereof.

In some embodiments, methods provided herein for treating COVID-19 in asubject in need thereof include administering a niclosamide compound, ora pharmaceutically acceptable salt thereof, and azithromycin. In someembodiments, about 500 mg azithromycin is administered to the subjectonce per day. In some embodiments, about 250 mg azithromycin isadministered to the subject once per day. In some embodiments, about 500mg azithromycin is administered to the subject on Day 1 and about 250 mgazithromycin is administered to the subject once per day on Days 2-5.See, e.g., Gautret et al. Int J Antimicrob Agents. 2020 Mar. 20:105949.

In some embodiments, methods provided herein for treating COVID-19 in asubject in need thereof include administering a niclosamide compound, ora pharmaceutically acceptable salt thereof, and hydroxychloroquine. Insome embodiments, about 200 mg hydroxychloroquine is administered to thesubject three times per day. In some embodiments, about 200 mghydroxychloroquine is administered to the subject three times per dayfor about 10 days. See, e.g., Gautret et al. Int J Antimicrob Agents.2020 Mar. 20:105949.

In some embodiments, methods provided herein for treating COVID-19 in asubject in need thereof include administering a niclosamide compound, ora pharmaceutically acceptable salt thereof, and chloroquine.

In some embodiments, methods provided herein for treating COVID-19 in asubject in need thereof include administering a niclosamide compound, ora pharmaceutically acceptable salt thereof, azithromycin, andhydroxychloroquine.

In some embodiments, methods provided herein for treating COVID-19 in asubject in need thereof include administering a niclosamide compound, ora pharmaceutically acceptable salt thereof, azithromycin, andchloroquine.

In some embodiments, the chloroquine is chloroquine phosphate (e.g.,ARALEN®). In some embodiments, the hydroxychloroquine ishydroxychloroquine sulfate (e.g., PLAQUENIL®).

Also provided herein are methods for treating COVID-19 in a subject inneed thereof, the methods comprising administering a niclosamidecompound, or a pharmaceutically acceptable salt thereof, and ananti-diabetic agent. In some embodiments, the anti-diabetic agent ismetformin.

Also provided herein are methods for treating COVID-19 in a subject inneed thereof, the methods comprising administering a niclosamidecompound, or a pharmaceutically acceptable salt thereof, and anangiotensin receptor inhibitor. In some embodiments, the angiotensinreceptor inhibitor is selected from eprosartan, olmesartan, valsartan,candesartan, losartan, telmisartan, irbesartan, azilsartan medoxomil,and a combination thereof.

Also provided herein are methods for treating COVID-19 in a subject inneed thereof, the methods comprising administering a niclosamidecompound, or a pharmaceutically acceptable salt thereof, and a statin.In some embodiments, the statin is selected from atorvastatin,fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, andsimvastatin, cerivastatin, mevastatin, and a combination thereof.

Niclosamide Compounds

Chemical Purity

In some embodiments, the niclosamide compounds (e.g., niclosamide) has achemical purity of greater than about 99.0%; e.g., greater than about99.5%; or greater than about 99.7%; or greater than about 99.8%.

In some embodiments, the niclosamide compounds (e.g., niclosamide) haveless than about 45 ppm of 5-chloro-salicylic acid; e.g., less than about30 ppm of 5-chloro-salicylic acid.

In some embodiments, the compound has less than about 50 ppm of2-chloro-4 nitro-aniline. In certain embodiments, the compound has lessthan about 10 ppm of 2-chloro-4 nitro-aniline.

In some embodiments, the compound has less than about 45 ppm of5-chloro-salicylic acid and less than about 50 ppm of 2-chloro-4nitro-aniline.

In some embodiments, the compound has less than about 30 ppm of5-chloro-salicylic acid and less than about 10 ppm of 2-chloro-4nitro-aniline.

In some embodiments, the compound has less than about 0.05% water. Incertain embodiments, the compound is substantially free of hydratedniclosamide solid forms. As a non-limiting example, the compound can beanhydrous niclosamide.

In some embodiments, purification can be carried out according to thefollowing process. Acetone and crude niclosamide are mixed in a vesseland heated to reflux (˜56° C.) until solids dissolve. The solution isclarified by filtration and transferred to a second vessel, heated to45° C. to 55° C. to dissolve the solids, cooled to −5° C. to 5° C. andstirred at this temperature for at least 2 hours. The solids arefiltered and washed with acetone. Crystallized niclosamide is obtainedafter vacuum drying of the solids at 70° C. IPC LOD testing is performedon the dry solids with a specification of <1.0%. If the LOD resultsare >1.0% the drying step may be repeated two additional times. IPCtesting is also performed to ensure the level of the starting material2-chloro-4-nitroaniline is <100 ppm. If the level of2-chloro-4-nitroaniline is >100 ppm, a second crystallization may beperformed.

In some embodiments, purity analysis can be achieved according to thefollowing procedure. Chromatograph: UPLC system consisting pump, diodearray; detector, autosampler, auto injector, and column cooler/heater,or equivalent. Column: Agilent Poroshell 120 EC-C18 column, 4.6×50 mm,2.7 μm or equivalent. Column Temperature: 35° C. Mobile phase A: 20 mMammonium acetate (pH 5.50). Mobile phase B: MeOH:ACN (70:30, v/v).Diluent: MeOH:DMSO (70:30, v/v).

Time Solvent A Solvent B (min.) (%) (%) 0.0 75 25 1.0 75 25 21.0 30 70

Flow rate: 1.0 ml/min. Injected volume: 3.00 μl. Preparation of standardand sample solutions. Niclosamide Standard Solutions: Concentration ofthis solution is nominally 0.8 mg/mL. Retention times: 5-Chlorosalicylicacid (2.9 minutes); 2-Chloro-4-nitroaniline (7.0 minutes); andNiclosamide (18.8 minutes).

Particle Size

In some embodiments, the compound has a reduced particle size (e.g., asachieved by techniques including but not limited to milling).

In some embodiments, niclosamide compounds having reduced particle sizecan be prepared by jet milling, e.g., using CMTI equipment NGMP-Mill-A,a 2-inch, pancake micronizer manufactured by Sturtevant; a flexiblecontainment unit was used during the milling process (Mill and Venturipressure both=50 psi; feed rate 96.0 g/hour).

In some embodiments of the foregoing, the compound has a particle sizerange of from about 0.1 μm to about 30 μm. In certain embodiments, thecompound has a particle size range of from about 0.1 μm to about 20 μm.In certain embodiments, the compound has a particle size range of fromabout 0.1 μm to about 10 μm.

The term “particle size distribution” of a powder, or granular material,or particles dispersed in fluid, as used within this application, is alist of values or a mathematical function that defines the relativeamounts of particles present, sorted according to size. The d(0.1),d(0.5) and d(0.9) values indicate that 10%, 50% and 90% of the particlesmeasured were less than or equal to the size stated. For example, valuesof d(0.1)=0.6, d(0.5)=3.1 and d(0.9)=7.3 mean that 10% of the particleswere less than or equal to 0.6 μm, 50% were less than or equal to 3.1μm, and 90% were less than or equal to 7.3 μm.

Particle Size Distribution (PSD) can be determined by laser diffractiontechnique, e.g., using a “MALVERN MASTERSIZER 2000” (standard rangebetween 0.020 and 2000.0 microns), model “APA 2000”, equipped with“Hydro 2000 sm” as dispersing unit. A representative procedure includes:approximately 50 mg of Niclosamide is dispersed manually into 25 ml ofwater; after dispersion the sample was sonicated with externalultrasound for two minutes (Ultrasonic frequency; 37 kHz—Elmasonic S100(H)—Elma Schmidbauer GmbH, Germany); the following operativeconditions/machine parameters are taken into account: Dispersant:Water+3 drops of Tyloxapol 1.5%; Background measurement time: 10seconds; Number of measurements cycles: 3 (to obtain average value);Stir speed (dispersing unit): 1500 rpm.

In some embodiments, the compound has a particle size distributionD(0.9) of from about 1.0 μm to about 15.0 μm. In certain embodiments,the compound has a particle size distribution D(0.9) of from about 1.0μm to about 10.0 μm. In certain embodiments, the compound has a particlesize distribution D(0.9) of from about 6.0 μm to about 8.0 μm (e.g.,about 7.3 μm (e.g., 7.3 μm)). In other embodiments, the compound has aparticle size distribution D(0.9) of from about 2.2 μm to about 3.2 μm.

In some embodiments, the compound has a particle size distributionD(0.1) of from about 0.1 μm to about 1.5 μm. In certain embodiments, thecompound has a particle size distribution D(0.1) of from about 0.1 μm toabout 1.0 μm. In certain embodiments, the compound has a particle sizedistribution D(0.1) of from about 0.3 μm to about 0.9 μm. In certainembodiments, the compound has a particle size distribution D(0.1) offrom about 0.45 μm to about 0.75 μm (e.g., about 0.6 μm (e.g., 0.6 μm)).

In some embodiments, the compound has a particle size distributionD(0.5) of from about 0.5 μm to about 6.0 μm. In certain embodiments, thecompound has a particle size distribution D(0.5) of from about 1.0 μm toabout 4.0 μm. In certain embodiments, the compound has a particle sizedistribution D(0.5) of from about 1.0 μm to about 2.0 μm. In certainother embodiments, the compound has a particle size distribution D(0.5)of from about 2.5 μm to about 3.5 μm (e.g., about 3.1 μm (e.g., 3.1μm)).

The parameter D(0.1) as used herein refers to the mesh size of a singlenotional sieve allowing 10% of the total of all particles of the sampleto pass. Thus D(0.1)=0.1-1.5 μm means that the upper limit of theparticle size range defining the 10% of smallest particles in the sampleis between 0.1 μm to 1.5 μm. Thus 10% of the total particles have aparticle size of not more than D(0.1) meaning in this case that theyhave a maximum size of 0.1 μm to 1.5 μm.

The parameter D(0.5) refers to the mesh size of a single notional sieveallowing 50% of the total of all particles of the sample to pass. ThusD(0.5)=0.5-6.0 μm means that the upper limit of the particle size rangedefining the notional half of the sample containing the smallerparticles is between 0.5 μm to 6.0 μm. Thus, 50% of the total of allparticles have a particle size of not more than D(0.5) meaning in thiscase that they have a maximum size of 0.5 μm to 6.0 μm.

The parameter D(0.9) refers to the mesh size of a single notional sieveallowing 90% of the total of all particles of the sample to pass i.e.only 10% of the sample is retained. Thus, D(0.9)=1.0-15.0 μm means thatthe lower limit of the particle size range defining the 10% of largestparticles in the sample is between 1.0 μm to 15.0 μm. Thus 90% of allparticles have a particle size of not more than D(0.9) meaning in thiscase that they have a maximum size of 1.0 μm to 15.0 μm.

In some embodiments, the compound has less than about 0.05% water (e.g.,as determined by Karl Fisher technique). In certain embodiments, thecompound is substantially free of hydrated niclosamide solid forms. As anon-limiting example, the compound can be anhydrous niclosamide.

In some embodiments, the compound is crystalline.

In some embodiments, the compound has a specific surface area of fromabout 5 m²/g to about 10 m²/g.

Non-Limiting Combination

Non-Limiting Combinations [A]

In some embodiments, the compound has a particle size distributionD(0.9) of from about 1.0 μm to about 10.0 μm, a particle sizedistribution D(0.5) of from about 1.0 μm to about 4.0 μm, and a particlesize distribution D(0.1) of from about 0.1 μm to about 1.0 μm.

In some embodiments, the compound has a particle size distributionD(0.9) of from about 6.0 μm to about 8.0 μm, a particle sizedistribution D(0.5) of from about 1.0 μm to about 4.0 μm, and a particlesize distribution D(0.1) of from about 0.3 μm to about 0.9 μl.

In some embodiments, the compound has a particle size distributionD(0.9) of from about 7.0 μm to about 7.5 μm (e.g., about 7.3 μm), aparticle size distribution D(0.5) of from about 2.5 μm to about 4.0 μm(e.g., about 3.1 μm), and a particle size distribution D(0.1) of fromabout 0.45 μm to about 0.75 μm (e.g., about 0.6 μm).

In some embodiments, the compound has a particle size distributionD(0.9) of about 7.3 μm, a particle size distribution D(0.5) of about 3.1μm, and a particle size distribution D(0.1) of about 0.6 μm.

In some embodiments, the compound has a particle size distributionD(0.9) of from about 2.2 μm to about 3.2 μm, a particle sizedistribution D(0.5) of from about 1.0 μm to about 4.0 μm, and a particlesize distribution D(0.1) of from about 0.3 μm to about 0.9 μl.

In some embodiments, the compound has a chemical purity of greater thanabout 99.0%, a particle size distribution D(0.9) of from about 1.0 μm toabout 10.0 μm, a particle size distribution D(0.5) of from about 1.0 μmto about 4.0 μm, and a particle size distribution D(0.1) of from about0.1 μm to about 1.0 μl.

In some embodiments, the compound has a chemical purity of greater thanabout 99.0%, a particle size distribution D(0.9) of from about 6.0 μm toabout 8.0 μm, a particle size distribution D(0.5) of from about 1.0 μmto about 4.0 μm, and a particle size distribution D(0.1) of from about0.3 μm to about 0.9 μl.

In some embodiments, the compound has a chemical purity of greater thanabout 99.0%, a particle size distribution D(0.9) of from about 2.2 μm toabout 3.2 μm, a particle size distribution D(0.5) of from about 1.0 μmto about 4.0 μm, and a particle size distribution D(0.1) of from about0.3 μm to about 0.9 μm.

In some embodiments, the compound has a chemical purity of greater thanabout 99.0%, a particle size range of from about 0.1 μm to about 30 μm,a particle size distribution D(0.9) of from about 1.0 μm to about 10.0μm, a particle size distribution D(0.5) of from about 1.0 μm to about4.0 μm, and a particle size distribution D(0.1) of from about 0.1 μm toabout 1.0 μm.

In some embodiments, the compound has a chemical purity of greater thanabout 99.0%, a particle size range of from about 0.1 μm to about 30 μm,a particle size distribution D(0.9) of from about 6.0 μm to about 8.0μm, a particle size distribution D(0.5) of from about 1.0 μm to about4.0 μm, and a particle size distribution D(0.1) of from about 0.3 μm toabout 0.9 μm.

In some embodiments, the compound has a chemical purity of greater thanabout 99.0%, a particle size range of from about 0.1 μm to about 30 μm,a particle size distribution D(0.9) of from about 2.2 μm to about 3.2μm, a particle size distribution D(0.5) of from about 1.0 μm to about4.0 μm, and a particle size distribution D(0.1) of from about 0.3 μm toabout 0.9 μm.

In certain embodiments of [A], the compound has a particle sizedistribution D(0.5) of from about 2.5 μm to about 3.5 μm.

In certain embodiments of [A], the compound has a particle sizedistribution D(0.5) of from about 1.0 μm to about 2.0 μm.

In certain embodiments of [A], the compound has a chemical purity ofgreater than about 99.5%; or a chemical purity of greater than about99.7%; or a chemical purity of greater than about 99.8%.

In certain embodiments of [A], the compound has less than about 45 ppmof 5-chloro-salicylic acid; or less than about 30 ppm of5-chloro-salicylic acid.

In certain embodiments of [A], the compound has less than about 50 ppmof 2-chloro-4 nitro-aniline; or less than about 10 ppm of 2-chloro-4nitro-aniline.

In certain embodiments of [A], the compound has less than about 45 ppmof 5-chloro-salicylic acid and less than about 50 ppm of 2-chloro-4nitro-aniline; or less than about 30 ppm of 5-chloro-salicylic acid andless than about 10 ppm of 2-chloro-4 nitro-aniline.

In certain embodiments of [A], the compound has less than about 0.05%water.

In certain embodiments of [A], the compound is substantially free ofhydrated niclosamide solid forms.

In certain embodiments of [A], the compound is anhydrous niclosamide.

In certain embodiments of [A], the compound is crystalline.

In certain embodiments of [A], the compound has a specific surface areaof from about 5 m²/g to about 10 m²/g.

Cocrystals of Niclosamide Compounds

Overview

In some embodiments, the niclosamide compounds (e.g., niclosamide) canbe in the form of a cocrystal that includes (i) a niclosamide compound(e.g., niclosamide) or a pharmaceutically acceptable salt thereof; and(ii) one or more pharmaceutically acceptable coformers. The term“co-crystal” as used herein refers to a crystalline material comprisedof two or more unique solids at room temperature in a stoichiometric ornon-stoichiometric ratio, which are held together in the crystal latticeby one or more non-covalent interactions (e.g., hydrogen bonds,pi-stacking, guest-host complexation and van der Waals interactions).

In some embodiments, at least one of the one or more non-covalentinteractions is a hydrogen bond. In certain of these embodiments, thechemical entity is the hydrogen bond donor, and one of one or morecoformers is the hydrogen bond acceptor. In other embodiments, thechemical entity is the hydrogen bond acceptor, and one of one or morecoformers is the hydrogen bond donor.

The co-crystals described herein can include one or more solvate (e.g.,water or an organic solvent containing one or more hydroxyl groups,e.g., a C₁-C₆ alcohol or diol, e.g., a C₁-C₆ alcohol or diol, e.g.,ethanol or propylene glycol) molecules in the crystalline lattice.However, solvates of chemical entities that do not further comprise acoformer (e.g., a solid conformer) are not encompassed by the co-crystaldefinition set forth in this disclosure.

In some embodiments, the cocrystal includes more than one coformer. Forexample, two, three, four, five, or more co formers can be incorporatedin a co-crystal with the chemical entity. The ratio of the chemicalentity to each of the one or more pharmaceutically acceptable coformersmay be stoichiometric or non-stoichiometric. As a non-limiting example,1:1, 1:1.5 and 1:2 ratios of chemical entity:coformer are contemplated.

The niclosamide compounds (e.g., niclosamide) and each of the one ormore pharmaceutically acceptable coformers may each be independentlyspecified as a free form, or more specifically, a free acid, free base,or zwitter ion; a salt, or more specifically for example, an inorganicbase addition salt such as sodium, potassium, lithium, calcium,magnesium, ammonium, aluminum salts or organic base addition salts, oran inorganic acid addition salts such as HBr, HCl, sulfuric, nitric, orphosphoric acid addition salts or an organic acid addition salt such asacetic, proprionic, pyruvic, malanic, succinic, malic, maleic, fumaric,tartaric, citric, benzoic, methanesulfonic, ethanesulforic, stearic orlactic acid addition salt; an anhydrate or hydrate of a free form orsalt, or more specifically, for example, a hemihydrate, monohydrate,dihydrate, trihydrate, quadrahydrate, pentahydrate; or a solvate of afree form or salt.

Coformers

In some embodiments, at least one of the one or more pharmaceuticallyacceptable coformers can form one or more hydrogen bonds with thechemical entity in the cocrystal. In some embodiments, at least one ofthe one or more pharmaceutically acceptable coformers can accept one ormore hydrogen bonds from the chemical entity in the cocrystal. In someembodiments, at least one of the one or more pharmaceutically acceptablecoformers can form one or more hydrogen bonds with the chemical entityin the cocrystal, and at least one of the one or more pharmaceuticallyacceptable coformers can accept one or more hydrogen bonds from thechemical entity in the cocrystal.

In some embodiments, at least one of the one or more pharmaceuticallyacceptable coformers comprises one or more functional groups selectedfrom the group consisting of: ether, thioether, hydroxy, sulfhydryl,aldehyde, ketone, thioketone, nitrate ester, phosphate ester,thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid,phosphonic acid, phosphinic acid, sulfonic acid, amido, primary amine,secondary amine, ammonia, tertiary amino, sp2 amino, thiocyanate,cyanamide, oxime, nitrile, diazo, haloalkyl, nitro, heterocyclic ring,heteroaryl ring, epoxide, peroxide, and hydroxamic acid.

In certain embodiments, each of the one of the one or morepharmaceutically acceptable coformers is independently selected fromacetamide, benzamide, (+/−)-limonene, 1-(phenylazo)-2-naphthylamine,1,2,6-hexanetriol,1,2-dimyristoyl-sn-glycero-3-(phospho-s-(1-glycerol)),1,2-dimyristoyl-sn-glycero-3-phosphocholine,1,2-dioleoyl-sn-glycero-3-phosphocholine,1,2-dipalmitoyl-sn-glycero-3-(phospho-rac-(1-glycerol)), 1,2-distearoyl-sn-glycero-3-(phospho-rac-(1-glycerol)), 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,5-naphthalene-disulfonic acid,1-hydroxy-2-naphthoic acid, 1-o-tolylbiguanide, 2-ethyl-1,6-hexanediol,4-aminobenzoic acid, 4-aminopyridine, 4-aminosalicylic acid,4-chlorobenzene-sulfonic acid, 4-ethoxyphenyl urea, 7-oxo-dhea, acacia,acacia mucilage, acacia syrup, acesulfame, acesulfame potassium,acetohydroxamic acid, acetone sodium bisulfate, acetylated lanolinalcohols, acetylated monoglycerides, acetylcysteine, acetyltributylcitrate, acrylates copolymer, acrylic acid-isooctyl acrylate copolymer,adenine, adipic acid, alanine, albumin aggregated, albumin colloidal,albumin human, albumins, alginic acid, alkyl ammonium sulfonic acidbetaine, alkyl aryl sodium sulfonate, allantoin, allopurineol, allylalpha-ionone, alpha-terpineol, alpha-tocopherol, alpha-tocopherolacetate, aminobenzoate sodium, amyl acetate, anethole, anhydrous citricacid, anhydrous dextrose, anhydrous lactose, anhydrous tribasic sodiumphosphate, anhydrous trisodium citrate, arginine, arlacel, asafetida,ascorbic acid, ascorbyl palmitate, asparagine, aspartame, aspartic acid,bacteriostatic sodium chloride injection, barium sulfate, benzalkoniumchloride, benzenesulfonic acid, benzethonium chloride, benzododeciniumbromide, benzoic acid, benzyl acetate, benzyl alcohol, benzyl benzoate,benzyl chloride, beta-carotene, betanaphthol, betose, bibapcitide,bismuth subcarbonate, bismuth subgallate, boric acid, brocrinat, butylstearate, butylated hydroxyanisole, butylated hydroxytoluene,butylparaben, butyric acid, C-11-1-aminocyclohexanecarboxylic acid,C12-15 alkyl lactate, caffeine, calcobutrol, caldiamide sodium,caloxetate trisodium, calteridol calcium, camphoric acid, capric acid,captan, captisol, carboxypolymethylene, carmine, carnauba wax, carnaubayellow wax, carrageenan, carrageenan calcium, carrageenan salt,carrageenan sodium, ceresin, ceteareth-12, ceteareth-15, ceteareth-30,cetearyl alcohol/ceteareth-20, cetearyl ethylhexanoate, ceteth-10,ceteth-2, ceteth-20, ceteth-23, cetostearyl alcohol, cetrimoniumchloride, cetyl alcohol, cetyl esters wax, cetyl palmitate,cetylpyridinium chloride, chlorocresol, chloroxylenol, cholesterol,chrysin, cinnamaldehyde, cinnamic acid, citrate, citric acid, citricacid monohydrate, clemizole, cocamide ether sulfate, cocamine oxide,coco betaine, coco diethanolamide, coco monoethanolamide,coco-caprylate, coco-glycerides, creatine, creatinine, cresol, cupricsulfate, cyclamic acid, cyclomethicone, cyclomethicone 5, cysteine,dalfampridine, decyl methyl sulfoxide, dehydroacetic acid, denatoniumbenzoate, deoxycholic acid, dextran, dextran 40, dextrates, dextrin,dextrose, dextrose monohydrate, diacetylated monoglycerides, diatrizoicacid, dibasic anhydrous sodium phosphate, dibasic sodium phosphate,dibasic sodium phosphate dihydrate, dibasic sodium phosphatedodecahydrate, dibasic sodium phosphate heptahydrate, dibutyl phthalate,dibutyl sebacate, diethyl phthalate, diethyl pyrocarbonate, diethylsebacate, diethylaminoethyl stearamide phosphate, diethylene glycolmonoethyl ether, diethylene glycol monomethyl ether, diethylhexylphthalate, diisopropyl adipate, diisopropyl dilinoleate,diisopropylbenzothiazyl-2-sulfenamide, dimethicone medical fluid 360,dimethyl isosorbide, dimethyl phthalate, dimethyl sulfoxide,dimethyldioctadecylammonium bentonite, dimethylglycine,dimethylsiloxane/methylvinylsiloxane copolymer, dinoseb-ammonium,dipropylene glycol, disodium cocoamphodiacetate, disodium hydrogencitrate, disodium laureth sulfosuccinate, disodium laurylsulfosuccinate, disodium oleamido monoethanolamine sulfosuccinate, disodium sulfosalicylate, disofenin, dl-a350 lactic acid,dl-acetyltryptophan, dl-alpha-tocopherol, dl-alpha-tocopherol acetate,dl-dipalmitoylphosphatidylglycerol, dl-distearoylphosphatidylcholine,dl-glutamic acid, dl-tartaric acid, d-mannose, dmdm hydantoin,docosanol, docusate sodium, d-ribose, edetate calcium disodium, edetatedisodium, edetate sodium, edetic acid, egg phosphatidyl glycerol, eggphospholipids, entsufon, entsufon sodium, epilactose, epitetracyclinehydrochloride, erythorbic acid, erythritol, ethanolamine hydrochloride,ethyl maltol, ethyl oleate, ethyl vanillate, ethyl vanillin,ethylenediamine dihydrochloride, ethylhexyl hydroxystearate,ethylparaben, eucalyptol, eugenol, exametazime, fatty acid esters, fattyacid glycerides, fatty acid pentaerythriol ester, fatty acids, fattyalcohol citrate, fatty alcohols, ferric chloride, ferric oxide,ferrosoferric oxide, ferrous fumarate, ferrous oxide, fluorescein,fructose, fumaric acid, fumaryl diketopiperazine, gadolinium oxide,galactaric acid, galactose, gamma cyclodextrin, genistein, gentisicacid, gentisic acid ethanolamide, gentisic acid ethanolamine, gluceptatesodium, gluconic acid, gluconolactone, glucosamine, glucose, glucuronicacid, glutamic acid, glutamic acid hydrochloride, glutamine, glutaricacid, glutathione, glyceryl caprylate, glyceryl dibehenate, glyceryldistearate, glyceryl isostearate, glyceryl laurate, glycerylmonostearate, glyceryl oleate, glyceryl palmitate, glycerylpalmitostearate, glyceryl ricinoleate, glyceryl stearate, glycerylstearate—laureth-23, glyceryl stearate/peg stearate, glycerylstearate/peg-100 stearate, glyceryl stearate/peg-40 stearate, glycerylstearate-stearamidoethyl diethylamine, glyceryl trioleate, glycine,glycine hydrochloride, glycol distearate, glycol stearate, glycolicacid, glycyrrhizin, guanidine hydrochloride, hexylresorcinol, hippuricacid, histidine, hyaluronate sodium, hydrocortisone, hydroquinone,hydrous-citric acid, hydroxyethylpiperazine ethane sulfonic acid,hydroxyoctacosanyl hydroxystearate, hydroxyprogesterone caproate,hydroxypropyl beta-cyclodextrin, hystrene, illicium anisatum, imidazole,imidurea, indigotindisulfonate sodium, iodoxamic acid, iofetaminehydrochloride, ipriflavone, isoleucine, isopropyl isostearate, isopropylmyristate, isopropyl myristate—myristyl alcohol, isopropyl palmitate,isopropyl stearate, isostearic acid, isostearyl alcohol, lactate,lactitol monohydrate, lactobionic acid, lactose, landalgine, lanolin,lauralkonium chloride, lauramine oxide, laureth sulfate, lauric acid,lauric diethanolamide, lauric myristic diethanolamide, lauroylsarcosine, lauryl lactate, lauryl sulfate, lecithin, leucine,levomenthol, levulinic acid, lidofenin, 1-sodium lactate, lysine, maleicacid, malic acid, malonic acid, maltitol, maltodextrin, maltol, maltoseanhydrous, mandelic acid, mannitol, maprofix, mebrofenin, medium-chaintriglycerides, medronate disodium, medronic acid, menthol, metacresol,methionine, methyl salicylate, methyl stearate,methylchloroisothiazolinone, methylisothiazolinone, methylparaben,methylparaben sodium, miripirium chloride, mono and diglyceride,monobasic sodium phosphate, monobasic sodium phosphate anhydrous,monobasic sodium phosphate dihydrate, monobasic sodium phosphatemonohydrate, monoglyceride citrate, monoglycerides, monosodium citrate,monosodium glutamate, monostearyl citrate, monothioglycerol, myristicacid, myristyl alcohol, myristyl lactate, niacinamide, nicotinamide,nicotinic acid, N-methyl glucamine, octanoic acid, oleth-20, oleylalcohol, oleyl oleate, orotic acid, oxalic acid, oxidronate disodium,oxyquinoline, palmitamine oxide, palmitic acid, pamoic acid,pentadecalactone, pentaerythritol cocoate, pentasodium pentetate,pentetate calcium trisodium, pentetic acid, phenol, phenonip,phenoxyethanol, phenylalanine, phenylethyl alcohol, phospholipid,piperazine, piperazine hexahydrate, procaine, product wat, proline,propenyl guaethol, propyl gallate, propylene carbonate, propyleneglycol, propylene glycol—lecithin, propylene glycol alginate, propyleneglycol diacetate, propylene glycol dicaprylate, propylene glycolmonolaurate, propylene glycol monopalmitostearate, propylene glycolpalmitostearate, propylene glycol ricinoleate, propyleneglycol/diazolidinyl urea/methylparaben/propylparben, propylparaben,propylparaben sodium, p-toluenesulfonic acid, pyridoxamine, pyridoxine(4-pyridoxic acid), quercetin, resveratrol, riboflavin, saccharin,saccharin calcium, saccharin sodium, saccharin sodium anhydrous,salicylic acid, saturated fatty acid esters, sebacic acid, serine,sodium 1,2-ethanedisulfonate, sodium 2-naphthalenesulfonate, sodiumacetate, sodium acetate anhydrous, sodium alginate, sodium alkylsulfate, sodium aluminium silicate, sodium ascorbate, sodium benzoate,sodium bicarbonate, sodium bisulfate, sodium bisulfate acetone, sodiumbisulfate, sodium bitartrate, sodium borate, sodium borate decahydrate,sodium carbonate, sodium carbonate decahydrate, sodium carbonatemonohydrate, sodium carboxymethyl beta-glucan (ds 065-085), sodiumcaseinate, sodium cellulose, sodium cetostearyl sulfate, sodiumchlorate, sodium chloride, sodium chloride injection, sodium cholesterylsulfate, sodium citrate, sodium citrate hydrous, sodium cocoylsarcosinate, sodium cyclamate, sodium desoxycholate, sodium dithionite,sodium dodecylbenzenesulfonate, sodium ethylparaben, sodium formaldehydesulfoxylate, sodium gluconate, sodium hydroxide, sodium hypochlorite,sodium iodide, sodium lactate, sodium laureth-2 sulfate, sodiumlaureth-3 sulfate, sodium laureth-5 sulfate, sodium lauroyl sarcosinate,sodium lauryl sulfate, sodium lauryl sulfoacetate, sodium metabisulfite,sodium nitrate, sodium oleate, sodium phosphate, sodium phosphatedihydrate, sodium phosphite, sodium polyacrylate, sodium polyacrylate(2500000 MW), sodium polymetaphosphate, sodium propionate, sodiumpyrophosphate, sodium pyrrolidone carboxylate, sodium starch glycolate,sodium starch glycolate type a corn, sodium starch glycolate type apotato, type B potato sodium starch glycolate, sodium stearate, sodiumstearyl fumarate, sodium succinate hexahydrate, sodium sulfate, sodiumsulfate anhydrous, sodium sulfate decahydrate, sodium sulfite, sodiumsulfosuccinated undecyclenic monoalkylolamide, sodium tartrate, sodiumthioglycolate, sodium thiomalate, sodium thiosulfate, sodium thiosulfateanhydrous, sodium trimetaphosphate, sodium tripolyphosphate, sodiumxylenesulfonate, sorbic acid, sorbitan, sorbitan isostearate, sorbitanmonolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitantristearate, sorbitol, squalane, stannous 2-ethylhexanoate,stearalkonium chloride, stearalkonium hectorite/propylene carbonate,stearamidoethyl diethylamine, stearates, stearic acid, stearicdiethanolamide, stearoxytrimethylsilane, stearyl alcohol, succinic acid,sucralose, sucrose, sucrose distearate, sucrose laurate, sucrosepalmitate, sucrose polyesters, sucrose stearate, sucrose syrup,sulfacetamide sodium, sulfobutylether beta-cyclodextrin, tagatose,tartaric acid, tegacid, tert-butylhydroquinone, tetrofosmin,theophylline, thimerosal, threonine, thymol, tocopherol, tocophersolan,tragacanth, triacetin, tribasic sodium phosphate, tribasic sodiumphosphate monohydrate, tribehenin, tricaprylin, triceteareth-4phosphate, triethanolamine lauryl sulfate, triethyl citrate,trihydroxystearin, trilaneth-4 phosphate, trilaureth-4 phosphate,trimyristin, tris, trisodium citrate dihydrate, trisodium hedta,tristearin, trolamine, tromantadine, tromethamine, tryptophan,tyloxapol, tyrosine, undecylenic acid, urea, urethane, ursodiol, valine,vanillin, versetamide, viscarin, vitamin E, vitamin E acetate, vitaminK5, xylitol, and zinc sulfate. See also U.S. Pat. No. 7,927,613, whichis incorporated herein by reference in its entirety. Otherpharmaceutically acceptable coformers include those delineated in the“Generally Regarded as Safe” (“GRAS”) and/or the US FDA “EverythingAdded to Food in the United States” (“EAFUS”) lists.

In certain embodiments, at least one of the one or more pharmaceuticallyacceptable coformers is selected from the group consisting of caffeine,urea, p-aminobenzoic acid, theophylline, benzyl benzoate, andnicotinamide. In other embodiments, the one or more pharmaceuticallyacceptable coformers is other than those selected from the groupconsisting of caffeine, urea, p-aminobenzoic acid, theophylline, benzylbenzoate, and nicotinamide. In other embodiments, the one or morepharmaceutically acceptable coformers is other than those selected fromthe group consisting of acetamide, benzamide, 2-aminothiazole, andisoniazide. In still other embodiments, the one or more pharmaceuticallyacceptable coformers is an amino acid (e.g., proline, e.g., D-proline orL-proline, or racemic proline). In another embodiment, the one or morepharmaceutically acceptable coformers is a 5-10 (e.g., 5-9, 5-6, or 5)membered heteroaryl, e.g., a nitrogen-containing heteroaryl, e.g.,imidazole.

In certain embodiments, at least one of the one or more pharmaceuticallyacceptable coformers is a second API. In certain of these embodiments,the second API is independently selected from (−)-amlodipine,(−)-halofenate, (R)-salbutamol, (R)-salbutamol, (R,R)-formoterol,(S)-doxazosin, (S)-fluoxetine, (S)-oxybutynin, 1,2-naphthoquinone,17-methyltestosterone, 17α-hydroxyprogesterone, 195mPt-cisplatin,1-naphthyl salicylate, 1-naphthylamine-4-, 1-theobromineacetic,1α-hydroxycholecalciferol, 2,4,6-tribromo-m-cresol,2,6-diamino-T-butyloxy-3,5′-azopyridine,2-[[[(1r)-2-(1h-imidazol-4-yl)-1-methylethyl]imino]phenylmethyl]-phenol,21-acetoxypregnenolone, 2-amino-4-picoline, 2-aminothiazole,2-ethoxybenzoic acid, 2-naphthol, 2-naphthyl benzoate, 2-naphthyllactate, 2-naphthyl salicylate, 2-p-sulfanilylanilinoethanol,2-thiouracil, 3′,3″,5′,5″-tetra-bromophenolphthalein,3-amino-4-hydroxybutyric acid, 3-Bromo-D-camphor, 3-Hydroxycamphor,3-O-Lauroylpyridoxol Diacetate, 3-pentadecylcatechol, 3-quinuclidinol,4,4′-oxydi-2-butanol, 4,4′-sulfinyldianiline, 4-amino-3-hydroxybutyricacid, 4-amino-3-phenylbutyric acid, 4-aminosalicylic acid,4-chloro-m-cresol, 4-hexylresorcinol, 4-salicyloylmorpholine,5′-nitro-2′-propoxyacetanilide, 5-aminolevulinic acid, 5-azacitidine,5-bromosalicyl-hydroxamic acid, 5F-DF-203, 5-FU, 5-HT3 antagonists,6-azauridine, 6-mercaptopurine, 8-hydroxyquinoline, 9-aminocamptothecin,A-151892, A-5021, abacavir, abaperidone, abarelix, abciximab, abecarnil,abetimus, abiraterone, ABLC, ABT-751, AC-5216, acadesine, acamprosate,acamprosate, acarbose, acebrophylline, acebutolol, acecainide,acecarbromal, aceclofenac, acedapsone, acediasulfone, acefylline,aceglutamide, aceglutamide, acemetacin, acenocoumarol, aceponate,acetal, acetamidoeugenol, acetaminophen, acetaminosalol, acetanilide,acetarsone, acetazolamide, acetiamine, acetohexamide, acetohydroxamicacid, acetophenazine, acetophenide, acetophenone, acetosulfone,acetoxolone, acetrizoat, acetyl, acetylcarnitine, acetylcholine,acetylcholine, acetylcysteine, acetylleucine, acetylpheneturide,acetylsalicylate, acetylsalicylic acid, aciclovir, acifran, acipimox,acitazanolast, acitretin, aclarubicin, aclatonium, aconitine, acranilacriflavine, acrisorcin, acrivastine, acrivastine, actagardinederivative, actarit, ACTH, acyclovir, adapalene, ADCON-L, adefovir,adefovir dipivoxil, adenoscan, adenosine triphosphate, ADEPT,adinazolam, adiphenine, ADL-10-0101, adrafinil, adrenalone,adrenochrome, adrogolide, AEOL-10150, aesthinol, AET, AF-2259,afloqualone, AG-041R, AG-2037, AGN-194310, agomelatine, ahistan,AHL-157, AIT-034, AIT-202, AJ-9677, AJG-049, ajmaline, akzo desogestrel,alacepril, alapivoxil, albaconazole, albendazole, albuterol, albutoin,alclofenac, alclometasone, alcuronium, aldioxa, aldol, aldosterone,alendronate, alendronic acid, alexidine, alfacalcidol, alfadolone,alfaxalone, alfentanil, alfimeprase, alfuzosin, alfuzosin, algestone,algestone, algin, alglucerase, alibendol, aliskiren, alitertinoin,alizapride, alkannin, alkofanone, allantoin, allobarbital, allopurinol,allyl isothiocyanate, allylestrenol, almagate, alminoprofen, almitrine,almotriptan, aloe-emodin, aloin, alosetron, alovudine, aloxiprin,alpha-, alpha-1 protease, alphaprodine, alpidem, alpiropride,alprazolam, alprenolol, alsactide, ALT-711, Althiazid, altinicline,altretamine, aluminium chloride hexahydrate, aluminon, aluminum acetatesolution, aluminum chlorate, aluminum hydroxychloride, aluminumpotassium sulfate, aluminum sodium sulfate, alusulf, alverine,alvimopan, alvocidib, ALX-0646, AM-24, AM-36, AM-477, amantadine,amantanium, ambazon, ambenonium, ambrisentan, ambroxol, ambucaine,ambuphylline, ambusid, ambutonium bromide, amcinonide, AMD-3100,amdinocillin, amdinocillin pivoxil, amdoxovir, amelubant, americaine,amezinium, amfenac, amidephrine, amidinomycin, amifostine, amiglumide,amikacin, amiloride, aminacrine, amineptine, aminitrozole, amino acidpreparations, aminocaproic acid, aminoglutethimide, aminoguanidine,aminohippurate, aminometradine, aminopentamide, aminophylline,aminopromazine, aminopyrine, aminoquinuride, aminorex, amiodarone,amiodipine, amiphenazole, amiprilose, amisulpride, amitriptyline,amitriptyline+ketamine, amitriptylinoxide, amlexanox, ammoniacum,ammoniated mercuric chloride, ammonium benzoate, ammonium mandelate,ammonium salicylate, ammonium valerate, amobarbital, amocarzine,amodiaquin, amorolfine, amoscanat, amosulalol, amotriphene, amoxapine,amoxicillin, amoxicillin+potassium clavulan, AMPAlex, amphetamine,amphetaminil, amphotericin B, ampicillin, ampiroxicam, ampligen,amprenavir, amrinose, amrubicin, amsacrine, amtolmetin guacil,amylocaine, AN-152, anabolic steroids, anagestone, anagrelide,anastrozole, anazolene, ancitabine, ancrod, andolast, androisoxazole,androstenediol, anecortave, anethole, anethole trithione, angiogenix,angiotensin, anhydrovinblastine, anidulafungin, anilerdine, aniracetam,anisindione, ani somycin, anisotropine, anistreplase, antazoline,anthiolimine, anthralin, anthramycin, anthrarobin, anthrax inhibitor,antiangiogenic, anticort, antidepressants, anti-invasins, antimonypotassium tartrate, antimony sodium thioglycollate, antimonythioglycollamide, antiprogestin, antipyrine, antipyrine salicylate,antithrombin III, anxiolytics, AP-521, AP-5280, apalcillin, apaziquone,apazone, apocodeine, apomine, apomorphine, apraclonidine, aprepitant,aprindine, aprobarbital, apronalide, aprotinin, aptiganel, AQ4N,aquavan, AR-116081, AR-A2, arachidonic acid, aranidipine, arbekacin,arbidol, arbutamine, arcitumomab, ardeparin, arecoline, argatroban,arginine, Ariflo aripiprazole, arofylline, arotinolol, arsacetin,arsenic trioxide, arsphenamine, arteether, arteflene, artemether,artemisinin, artemotil, artesunate, arzoxifene, AS-3201, ASA,ascaridole, ascorbic acid, asenapine, asimadoline, asocarboxazid,asoprisnil, asoxime, aspartic acid, aspidin, aspidinol, aspirin, aspirindipyridamole, aspoxicillin, AST-120, astemizole, asulacrine, AT-1015,atamestane, atazanavir, atenolol, atenolol+chlorthalidone,atenolol+nifedipine, atevirdine, atipamezole, atiprimod dimaleate,ATL-146e, atomoxetine, atorvastatin, atosiban, atovaquone,atovaquone+proguanil, atracurium, atrasentan, atrial natriuretic,atrolactamide, atropine, augmentin, auranofin, aurothioglucose,avasimibe, avobenzone, AWD-12-281, azacitidine, azacyclonol,azanidazole, azapropazone, azaserine, azasertron, azatadine,azathipprine, AZD-4282, AZD-6140, azelaic acid, azelastine,azelnidipine, azidamfenicol, azidocillin, azimilide, azintamide,azithromycin, azlocillin, azosemide, aztreonam, azulene, bacampicillin,bacitracin, baclofen, baicalein, balofloxacin, balsalazide, bambuterol,bamethan, bamifylline, bamipine, barbital, barnidipine, BAS-118, basicalumina, baslilximab, batimastat, batroxobin, Bay-41-2272, Bay-41-8543,BAY-43-9006, BAY-57-1293, bazedoxifen, BBR-3464, BBR-3576, BBR-3610,BCH-1868, bebeerine, beclamide, beclometasone, befloxatone, befunolol,bemegride, benactyzine, benazepril, bencyclane, bendazac,bendroflumethiazide, benetonide, benexate, benfluorex, benfotiamine,benfurodil, benidipine, benorylate, benoxaprofen, benoxinate,benperidol, benproperine, benserazide, bentazepam, bentiromide,bentoquatam, benzafibrate, benzalkonium, benzarone, benzathine,benzbromarone, benzethonium, benzetimide, benzilonium, benziodarone,benznidazole, benzocaine, benzoctamine, benzonatate, benzoxoniumchloride, benzoyl peroxide, benzoylpas, benzphetamine, benzpiperylon,benzquinamide, benzthiazide, benztropine, benzydamine, benzyl benzoate,benzylhydrochloro-thiazide, benzylmorphine, bephenium, bepotastine,bepridil, beraprost, berberine, bergapten, bermoprofen, besipirdine,betahistine, betaine, betamethasone, betamipron, betasine, betaxolol,betazole, bethanechol, bethanidine, betoxycaine, bevantolol, bevonium,bexarotene, bezitramide, BG-9928, BIA-2-024, BIA-2-093, BIA-3-202,bialamicol, biapenem, bibenzonium, bibrocathol, bicalutamide,bicifadine, bicisate, bicyclic, bidisomide, bietamiverine, bietanautine,bietaserpine, bifermelane, bifluranol, bifonazole, bimatoprost,bimoclomol, bimosiamose, binifibrate, binodenoson, biomed-101, biotin,biperiden, biriperone, birlcodar, bisacodyl, bisantrene, bisbentiamine,bisdequalinium, bismuth, bismuth, bismuth, bismuth aluminate, bismuthethyl, bismuth sodium, bismuth sodium triglycollamate, bismuthsubcarbonate, bismuth subgallate, bismuth subnitrate, bismuthsubsalicylate, bisoprolol, bisoprolol+HCTZ,bisoprolol+trichloromethiazide, bisoxatin, bithionol, bitolterol,bitoscanat, BL-3875, bleomycin, blonanserin, BMS-184476, BMS-387032,BN-82451, BNP-7787, BO-653, bolandiol, bolasterone, boldenone,bopindolol, bornyl chloride, bornyl salicylate, bortezomib, bosentan,bradycor, brain natriuretic, brallobarbital, brasofensine, brequinar,bretylium, brilliant green, brimonidine, brinzolamide, brivudin,brodimoprim, bromazepam, bromfenac, bromhexine bromide, bromindione,bromisovalum, bromocriptine, bromo-diphenhydramine, bromoform,bromopride, bromo-salicychloranilide, bromperidol, brompheniramine,broparoestrol, bropirimine, brostallicin, brotizolam, brovincamine,broxyquinoline, brozuridine, brucine, bucetin, bucillamine, bucindolol,bucladesine, buclizine, buclosamide, bucolome, bucricaine, bucumolol,budesonide, budesonide+formoterol, budipine, budralazine, bufeniode,bufetolol, bufexamac, buflomedil, buformin, bufuralol, bumadizon,bumetanide, bunaftine, bunamiodyl sodium, bunazosin, bunitrolol,bupivacaine, bupranolol, buprenorphine, bupropion, buramate, buserelin,buspirone, busulfan, busulfan, butabarbital, butacaine, butacetin,butalamine, butalbital, butallylonal, butamben, butamirate,butanilicaine, butaperazine, butaverine, butazolamide, butedronic acid,butenafine, butethal, butethamate, butethamine, buthalital, buthiazide,butibufen, butidrine, butobendine, butoconazole, butoctamide,butofilolol, butorphanol, butoxycaine, butriptyline, butropium,butylthiolaurate, butyrate propio, buzepide, BVT-5182, BXT-51072,C-1311, cabergoline, cabergoline, cacodylic acid, cactinomycin,cadexomer iodine, cadmium salicylate, cadralazine, cafaminol, caffeine,calcifediol, calcipotriene, calcipotriol, calcipotriol+beclometasone,calcitriol, calcium 3-aurothio-2-propanol-1-sulfonate, calciumacetylsalicylate, calcium bromolactobionate, calcium carbonate, calciumgluconate, calcium glycerophosphate, calcium hopantothenate, calciumiodobehenate, calcium iodosterate, calcium lactate, calcium levulinate,calcium mesoxalate, calcium N-carbamoylaspartate, calcium polycarbophil,calcium propionate, calcium succinate, caldaret, calusterone, camazepam,camostat, camphor, camphorate, camphotamide, camptothecin, candesartan,candesartan cilexetil, candoxatril, canertinib, canrenone, cantharidin,cantuzumab mertansine, capecitabine, capobenic acid, capravirine,capromab, capsaicin cream, captodiamine, captopril, captopril+HCTZ,capuride, carabersat, caramiphen, carazolol, carbachol, carbamazepine,carbamide peroxide, carbarsone, carbaryl, carbazochrome, carbendazim,carbenicillin, carbenoxolone, carbetapentane, carbicarb, carbidopa,carbidopa+levodopa-1, carbimazole, carbinoxamine, carbocloral,carbocysteine, carbon tetrachloride, carbonate gel, carboplatin,carboprost, carboprost, carboquone, carbromal, carbubarb, carbutamide,carbuterol, carfimate, carglumic acid, cargutocin, carindacillin,cariporide, cariporide, carisoprodol, carmofur, carmoxirole, carmustine,carnitine, caroverine, caroxazone, carphenazine, carpipramine,carprofen, carsalam, carteolol, carticaine, carubicin, carumonam,carvacrol, carvedilol, carvone, cascarillin, caspofungin, catechin,cathepsin K inhibitors, cathepsin S inhibitors, CC-401, CCI-779, CCR5antagonists, CDC-394, CDC-801, CEE-03-310, cefactor, cefadroxil,cefalexin, cefalexin pivoxil, cefamandole, cefatrizine, cefazedone,cefazolin, cefbuperazone, cefcapene pivoxil, cefclidin, cefdinir,cefditoren pivoxil, cefepime, cefetamet, cefetamet pivoxil, cefixime,cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid, cefoperazone,cefoperazone+sulbactam, ceforanide, cefoselis, cefotazime, cefotetan,cefotiam, cefotiam hexetil, cefoxitin, cefozopran, cefpimizole,cefpiramide, cefpirome, cefpodoxime, cefprozil, cefroxadine, cefsulodin,ceftazidime, cefteram, ceftezole, ceftibuten, ceftizoxime, ceftizoxime,ceftriaxone, cefuroxime, cefuroxime axetil, cefuzonam, celecoxib,celgosivir, celiprolol, cellulose ethyl, CEP-1347, CEP-701,cephacetrile, cephaeline, cephalexin, cephaloglycin, cephaloridine,cephalosporin C, cephalothin, cephapirin, cephradine, cerivastatin,ceronapril, certoparin, ceruletide, cerviprost, cetalkonium, cetamolol,cethexonium, cethromycin, cetiedil, cetirizine, cetirizine,cetirizine+pseudoephedrine, cetotiamine, cetoxime, cetraxate,cetrimonium, cetrorelix, cetyldimethylethyl-ammonium, cetylpyridinium,cevimeline, CG-1521, chaulmoogric acid, chenodiol, CHF-3381,chlophedianol, chloracizine, chloral, chlorambucil, chloramine-B,chloramine-T, chloramino-chloramphenicol, chlorazanil, chlorbenzoxamine,chlorbetamide, chlorcyclizine, chlordantoin, chlorguanide, chlorhexadol,chlorhexidine, chloriazepoxide, chlori sondamine, chlormadinone,chlormerodrin, chlormezanone, chlormidazole, chlornaphazine,chloroazodin, chlorophyll, chloroprednisone, chloroprocaine,chloropyramine, chloroquine, chlorothen, chlorothiazide,chlorotrianisene, chloroxine, chloroxylenol, chlorozotocin,chlorphenamine, chlorphenesin, chlorpheniramine, chlorphenoxamide,chlorphenoxamine, chlorphentermine, chlorproethazine, chlorproguanil,chlorproguanil+dapsone, chlorpromazine, chlorpropamide, chlorprothixene,chlorquinaldol, chlortetracycline, chlorthalidone, chlorthenoxazine(e),chlorzoxazone, cholic acid, choline, choline theophyllinate,choline-L-alfoscerate, chromocarb, chromonar, chrysoidine, CHS-828,CI-1031, CI-1040, cibenzoline, ciclesonide, cicletanine, ciclonicate,ciclopirox, ciclosidomine, ciclosporin A, cidofovir, cifenline,cilansetron, cilastatin, cilazapril, cilengitide, cilnidipine,cilomilast, cilostazol, cimetidine, cimetropium, cinacalcet,cinchonidine, cinchonine, cinchophen, cinepazet, cinepazide, cinepazide,cinitapride, cinmetacin, cinnamedrine, cinnarizine, cinolazepam,cinoxacin, cinoxate, cinromide, cioteronel, cipamfylline, cipralisant,ciprofibrate, ciprofloxacin, ciprofloxacin+ciramadol, cisapride,cisatracurium, cisplatin, citalopram, citicoline, Citiolone, citrate,citric acid, citrulline, cizolirtine, CJ-13610, CKD-602, cladribine,clanobutin, clarithromycin, clavulan, clavulanate disodium, clavulanicacid, clebopride, clemastine, clemizol, clenbuterol, clentiazem,clevidipine, clevudine, clidanac, clidinium, clinafloxacin, clindamycin,clindamycin, clindamycin+tretinoin, clinofibrate, clinprost, clobazam,clobenfurol, clobenoside, clobenzepam, clobenzorex, clobenztropine,clobetasol, clobetasone, clobutinol, clocapramine, clocinizine,cloconazole, clocortolone, clodronate, clodronic acid, clofarabine,clofazimine, clofenamide, clofibrat, clofibric acid, cloflucarban,clofoctol, cloforex, clomacran, clomestrone, clometacin, clomethiazole,clometocillin, clomiphene, clomipramine, clomocycline, clonazepam,clonidine, clonitazene, clonitrate, clonixin, clopamid, clopenthixol,cloperastine, clopidogrel, clopirac, cloprednol, cloranolol, clorazepicacid, clorexolone, cloricromene, clorindione, clorprenaline,clortermine, clospirazine, clostebol, clothiapine, clotiazepam,clotrimazole, clotrimazole+betamethasone, cloxacillin, cloxazolam,cloxotestosterone, cloxyquin, clozapine, CMI-392, CMT-3, CNI-1493,CNS-5161, cobamamide, cocaethylene, cocaine, codeine, cofactor,colchicine, colesevelam, colestilan, colestipol, colforsin daropate,colfosceril, collagraft, colocynthin, colpormon, coluracetam,combretastatin A-4 prodrug, compound B, conivaptin conjugate,connettivina, convallatoxin, coparaffinate, corticorelin ovine,corticosterone, cortisone, cortivazol, cosyntropin, cotarnine, cotinine,co-trimazine, coumetarol, CP-248, CP-461, CPC-211, CPI-1189, CRA-0450,creatinol-O-phosphate, CRL-5861, crobenetine, croconazole, cromoglicicacid, cromolyn, cropropami de, crotamiton, crotethamide, crystacide,CS-502, CS-758, CS-834, CT-052923, CT-32228, cupric citrate,cuproxoline, CVT-2584, CX-659S, cyacetacide, cyamemazine, cyanidin,CYC400, cyclacillin, cyclandelate, cyclazocine, cyclexanone,cyclexedrine, cyclidrol, cyclin D1 inhibitors, cyclizine, cyclobarbital,cyclobendazole, cyclobenzaprine, cyclobutyrol, cyclocumarol, cyclodrine,cyclofenil, cycloguanil, cyclomethycaine, cycloniumelodide,cyclopentamine, cyclopenthiazide, cyclopentobarbital, cyclopentolate,cyclophosphamide, cyclopiroxalamine, cycloserine, cyclothiazide,cyclovalone, cymarin, cymserine, cynarin(e), cyp26 inhibitors,cyproheptadine, cyproterone, cysteamine, cystic fibrosis ther,cytarabine, D-24851, D-4418, DA-5018, DA-6034, DA-7867, DA-7911,DA-8159, dacarbazine, daclizumab, dactinomycin, dalbavancin,dalfopristin, dalfopristin+quinupristin, dalteparin, daltroban,danaparoid, danazol, danthron, dantrolene, dapiprazole, dapivirine,dapoxetine, dapsone, daptomycin, darbepoetin alfa, darifenacin,daunorubicin, DAX<SciClone, DB-67, D-camphocarboxylic, DCF-987, DDT,deaminooxytocin, deanol, debrisoquin, decamethonium, decimemide,decitabine, declopramide, deferiprone, deferoxamine, deflazacort,defosfamide, degarelix, dehydroascorbic acid, dehydroemetine,dehyrdocholic acid, delapri+manidipine, delapril, delavirdine,delmadinone, delmopinol, delorazepam, delucemine, demanyl, demecarium,demeclocycline, demecolcine, demegestone, demexiptilline, denaverine,dendrimers, denileukin diftitox, denopamine, denopterin, deoxycholicacid, deoxycorticosterone, deoxydihydro-streptomycin, deoxyepinephrine,depreotide, depsipeptide, deptropine, dequalinium, dersalazine,deserpidine, desferrioxamine, desflurane, desipramine, deslanoside,desloratadine, deslorelin, desmopressin, desogestrel,desogestrel+estradiol, desogestrel+ethinylestrad (1), desomorphine,desonide, desoximetasone, detaxtran, devacade, dexamethasone,dexanabinol, dexecadotril, dexefaroxan, dexetimide, dexibuprofen,dexketoprofen, dexloxiglumide, dexmedetomidine, dexmethylphenidate,dexpanthenol, dexrazoxane, dextran-1, dextranomer, dextroamphetamine,dextromethorphan, dextromoramide, dextropropoxyphene, dezocine, DF-1012,DFA-IV, D-fenchone, D-glucuronolactone, Diab II, diacerein, diampromide,diamthazole, diathymosulfone, diatrizoate, diazepam, diaziquone,diazoxide, dibekacin, dibenzepin, dibromopropamidine, dibucaine,dichloralphenazone, dichloramine T, dichlorisone, dichlorobenzylalcohol, dichlorohydrin, dichlorophen, dichlorophenarsine,dichlorphenamide, diclofenac, diclofenac+HA, dicloxacillin, dicoumarol,dicumarol, dicyclomine, didanosine, dideoxyadenosine, didox, dienestrol,dienogest, dienogest+estradiol, diethadione, diethazine, diethylamide,diethylbromo-acetamide, diethylcarbamazine, diethylpropion, diethylstilbestrol, difemerine, difenamizole, difenoxin, difenpirami de,diflomotecan, diflorasone, difloxacin, diflucortolone, diflunisal,difluprednate, digitalin, digitoxin, digoxin, dihexyverine,dihydralazine, dihydrocodeine, dihydrocodeinone enol,dihydroergocryptine, dihydroergocryptine, dihydroergotamine,dihydromorphine, dihydrostreptomycin, dihydrotachysterol,dihydroxyaluminum, diisopromine, diisopropyl paraoxon, diisopropylamine,dilazep, dilevalol, diloxanide, diltiazem, dimecrotic acid, dimefline,dimeglumine, dimemorfan, dimenhydrinate, dimenoxadol, dimepheptanol,dimercaprol, dimetacrine, dimethadione, dimethazan, dimethindene,dimethisoquin, dimethisterone, dimethocaine, dimethoxanate, dimethylsulfoxide, dimethylthiambutene, dimetofrine, dimorpholamine,dinoprostone, diosmectite, diosmin, dioxadrol, dioxaphetyl,dioxethedrine, dioxybenzone, diphemanil, diphenadione, diphencyprone,diphenhydramine, diphenidol, diphenoxylate, diphenylpyraline,diphetarsone, diphtheria & tetanus toxoids and acellular pertussisvaccine adsorbed, dipipanone, dipivefrin, dipyridamole, dipyridamole,dipyrocetyl, dipyrone, diquafosol, dirithromycin, disodium pamidronate,di sofenin, di sopyramide, di stigmine, di sulfamide, disulfiram,ditazol, dithiazanine, dithranol, ditiocarb, dixanthogen, dixyrazine,DJ-927, DK-507k, DL-Lactic Acid, DMDC, DMXAA, DNA Stealth, dobesilate,dobutamine, docarpamine, docetaxel, docosahexaenoic acid, docosanol,docusate, dofetilide, dolasetron mesilate, domiodol, domiphen,domitroban, domperidone, donepezil, donitriptan, dopamine, dopexamine,doramapimod, doranidazole, doripenem, dorzolamide, dorzolamide+timolol,dosmalfate, dosulepine, dotarizine, dothiepin, doxacurium, doxapram,doxazosin, doxefazepam, doxenitoin, doxepin, doxercalciferol,doxifluridine, doxofylline, doxorubicin, doxycycline, doxylamine,DPC-817, DPI-3290, DQ-113, drofenine, droloxifene, drometrizole,dromostanolone, dronabinol, dronedarone, droperidol, droprenilamine,dropropizine, drospirenone, drotaverine, drotebanol, droxicam,droxidopa, droxidopa, DU-125530, duloxetine, duramycin, durapatite,dutasteride, DW-1141, DW-286a, DW-471, DX-9065a, DY-9760e, dyclonine,dydrogesterone, dymanthine, dyphyllin, E-1010, E-2101, E2F antagonists,E-3620, E-5564, E-5842, E-6259, EAA-90, ebastine, eberconazole,ebrotidine, ebselen, eburnamonine, ecabapide, ecabet, ecadotril,ecgonidine, ecgonine, echothiophate, econazole, ecopipam, ecraprost,ectylurea, ED-71, edaravone, edatrexate, edetate calcium disodium,edetate disodium, edetate sodium, edetate trisodium, edonentan,edotreotide, edoxudine, edrecolomab, edrophonium, efalith, efaproxiral,efavirenz, efletirizine, eflornithine, efloxate, eflucimibe,efonidipine, EGIS-7229, eglumegad, egualen, elarofiban, elcatonin,elcosapentaenoic acid, eledoisin, eletriptan, elgodipine, ellagic acid,elliptinium, eltoprazine, elvucitabine, elzasonan, embelin, embramine,emedastine, emepronium, emetine, emitefur, EMM-210525, emodin,emorfazone, EMR-62203, emtricitabine, emylcamate, enalapril,enalaprilat, enallylpropymal, encainide, enciprazine, endralazine,enfenamic acid, enflurane, enilconazole, eniluracil, ENMD-0995,enocitabine, enol-3-IPA, enoxacin, enoxaparin, enoximone, enoxolone,enprostil, enrasentan, entacapone, entecavir, enviomycin, eoinephrine,epalrestat, epavir, EPC-K1, eperi sone, epervudine, ephedrine,epicillin, epimestrol, epinastine, epirizole, epirubicin, epitiostanol,eplerenone, eplivanserin, epoprostenol, epostane, eprazinone,epristeride, eprosartan, eprozinol, eptapirone, eptaplatin,eptastigmine, eptazocine, eptifibatide, equilenin, equilin, ERA-923,erdosteine, ergocornine, ergocorninine, ergoloid mesylates, ergonovine,ergosterol, ergotamine, eritadenine, erlotinib, ertapenem, erythrityltetranitrate, erythrocentaurin, erythromycin acistrate, erythromycinerythrophleine, erythromycin estolate, erythromycin glucoheptonate,erythromycin lactobionate, erythromycin propionate, erythromycinstearate, erythromycin stinoprate, esaprazole, escitalopram, esculin,eseridine, esmolol, esomeprazole, estazolam, ester, estradiol,estradiol, estramustine, estriol, estrogen, estrone, eszopiclone,etafedrine, etafenone, etamiphyllin, etanercept, etanidazole,etaqualone, eterobarb, ethacridine, ethacrynic acid, ethadion,ethambutol, ethamivan, ethamsylate, ethanolamine, ethaverine,ethchlorvynol, ethenzamide, ethiazide, ethinamate, ethinyl estradiol,ethinyl estradiol, ethinyl estradiol, ethionamide, ethisterone,ethoheptazine, ethopropazine, ethosuximide, ethotoin, ethoxzolamide,ethybenztropine, ethyl alcohol, ethyl biscoumacetate, ethyl chloride,ethyl dibunate, ethyl ether, ethyl icosapentate, ethyl loflazepate,ethyl loflazepate, ethylamine, ethylene, ethylestrenol, ethylidene,ethylmethyl-thiambutene, ethylmorphine, ethylnorepinephrine, ethynodiol,ethynylcytidine, etidocaine, etidronate, etidronic acid, etifelmin,etifoxine, etilefrin, etilevodopa, etiprednol, etiroxate, etizolam,etodolac, etodroxizine, etofenamate, etofibrate, etofylline, etofyllineclofibrate, etofylline nicotinate, etoglucid, etomidate, etomidoline,etonitazene, etonogestrel, etoperidone, etoposide, etoposide phosphate,etoricoxib, etoxadrol, etozolin, etretinate, etryptamine, etymemazine,eucatropine, eugenol, EUK-134, EUK-189, evans blue, everolimus,exalamide, exametazime, exatecan, exemestane, exifone, exisulind,Exosurf ezetimibe, Factor IX, Factor VIII, Factor XIII, fadolmidine,fadrozole, falecalcitriol, famciclovir, famotidine, fampridine,fandofloxacin, fantofarone, faropenem, faropenem daloxate, fasidotril,fasudil, fazadinium bromide, febarbamate, febuprol, febuxostat,fedotozine, felbamate, felbinac, felodipine, felypressin, femoxetine,fenbenicillin, fenbufen, fenbutrazate, fencamfamine, fencamine,fenclozic acid, fendiline, fendosal, fenethylline, fenfluramine,fenipentol, fenofibrate, fenoldopam, fenoprofen, fenoterol, fenoverine,fenoxazoline, fenoxedil, fenozolone, fenpentadiol, fenpiprane,fenpiverinium, fenproporex, fenquizone, fenretinide, fenspiride,fentanyl, fentiazac, fenticlor, fenticonazole, fentonium bromide,fepradinol, feprazone, ferric sodium edetate, ferrioxamine B,ferrocholinate, ferrous gluconate, ferumoxytol, fesoterodine,fexofenadine, fibrostat, fidarestat, fiduxosin, finasteride, finrozole,fipexide, FK-960, flavopiridol, flavoxate, flecainide, fleroxacin,flesinoxan, flibanserin, floctafenine, flomoxef, flopropione,florantyrone, flosequinan, floxacillin, floxuridine, fluacizine,fluanisone, fluarizine, fluasterone, fluazacort, flucloronide,flucloxacillin, fluconazole, flucytosine, fludarabine, fludeoxyglucoseF18, fludiazepam, fludrocortisone, flufenamic acid, fluindione,flumazenil, flumecinol, flumequine, flumethasone, flumethiazide,flunisolide, flunitrazepam, flunoxaprofen, fluocinolone acetonide,fluocinolone SAL, fluocinonide, fluocortin butyl, fluocortolone,fluorescein, fluoresone, fluorometholone, fluorosalan, fluorouracil,fluoxetine, fluoxymesterone, flupentixol, fluperolone, fluphenazine,flupirtine, fluprednidene acetate, fluprednisolone, fluproquazone,flurandrenolide, flurazepam, flurbiprofen, flurithromycin, flurogestone,flurothyl, fluroxen, fluspirilene, flutamide, flutazolam, fluticasone,flutoprazepam, flutrimazole, flutropium bromide, fluvastatin,fluvoxamine, folic acid, folinic acid, fomepizole, fominoben,fomivirsen, fomocaine, fonazine, fondaparinux, formebolone, formestane,formocortal, formoterol, fosamprenavir, foscarnet, fosfestrol,fosfluconazole, fosfomycin, fosfomycin, fosfosal, fosinopril,fosphenytoin, fotemustine, fropenem, frovatriptan, fructose,fructose-1,6-diphosphate, FTC, FTY-720, fudosteine, fulvestrant,fumagiline, fumagillin, furaltadone, furazabol, furazolidone, furazoliumchloride, furonazide, furosemide, fursultiamine, furtrethonium, fusidicacid, G1, YM BioSciences, G25, GABA-A Alpha5, gabapentin, gabexate,gaboxadol, gadobenat, gadobutrol, gadodiamide, gadolinium, gadopenteticacid, gadoteridol, gadoversetamide, gadoxetic acid, galantamine,galanthamine, galarubicin, gallamine triethiodide, gallic acid, galliummaltolate, gallium nitrate, gallopamil, ganaxolone, ganciclovir,ganirelix, ganstigmine, gantofiban, garenoxacin, garnocestim,gatifloxacin, gefarnate, gefitinib, gemcabene, gemcitabine, gemeprost,gemfibrozil, gemifloxacin, gentamicin, gentian violet, gentiopicrin,gentisic acid, gepefrine, gepirone, gestodene, gestodene+ethinylest,gestonorone caproate, gestrinone, gimatecan, giractide, gitoxin,GL-406349, Glafenine, glatiramer, Glibornuride, gliclazide, glimepiride,glipizide, gliquidone, glisolamide, glisoxepid, globulin (human),glucametacin, glucoheptonic acid, gluconic acid, glucosamine,glucosulfone, glufosfamide, glutamic acid, glutaraldehyde, glutethimide,glyburide, glybuthiazol(e), glybuzole, glycerol, glycerophosphate,glycocyamine, glycol salicylate, glyconiazide, glycopyrrolate,glyhexamide, glymidine, glypinamide, GMDP, gold sodium, goserelin,GPI-1485, GPI-5693, graftskin, granisetron, grepafloxacin, griseofulvin,guaiacol, guaiapate, guaiazulene, guaifenesin, guaimesal,gualacolsulfonate, guamecycline, guanabenz, guanadrel, guanethidine,guanfacine, guanoxabenz, guanoxan, gugulipid, gusperimus, GW-280430A,GW-320659, GYKI-16084, hachimycin, halazepam, halcinonide, halobetasol,halofantrine, halometasone, haloperidol, halopredone, haloprogin,halopropane, halothane, haloxazolam, harkoseride, HE-2000, healos,hematoporphyrin, hepronicate, heptabarbital, heptaminol, hetacillin,hetastarch, hexacetonide, hexachlorophene, hexadimethrine,hexafluorenium, hexamethonium, hexamidine, hexapropymate, hexedine,hexestrol, hexestrol Bis(β-diethylaminoethyl ether), hexethal,hexetidine, hexobarbital, hexobendine, hexocyclium methyl sulfate,hexoprenaline, hextend, hexylcaine, HF-0299, HGP-2, HGP-6A, hidrosmin,histamine, Hi stapyrrodine, histrelin, HM-101, HMN-214, homatropine,homocamfin, homochlorcyclizine, hopantenic acid, HP-228, huperzine A,hyaluronan, hycanthone, hydnocarpic acid, hydralazine, hydrastine,hydrastinine, hydrochlorothiazide, hydrocodone, hydrocortamate,hydrocortisone, hydrocortisone, hydroflumethiazide, hydromorphone,hydroquinidine, hydroquinine, hydroquinone, hydroxid, hydroxocobalamin,hydroxyamphetamine, hydroxychloroquine, hydroxydione, hydroxyethylether, hydroxynaphthoate, hydroxypethidine, hydroxyphenamate,hydroxypropyl cellulose, hydroxystilbamidine, hydroxytetracaine,hydroxyzine, Hylan G-F 20, hymecromone, hyoscyamine, hypericin, IACFT,ibandronic acid, ibopamine, ibopamine, Ibritumomab, ibrolipim,ibudilast, Ibufenac, ibuprofen, ibuprofen piconol, ibuproxam, ibutilide,ICA-17043, icodextrin, idarubicin, Idazoxan, IdB-1016, idebenone,IDN-5109, idoxifen, idraparinux, idrocilamide, ifenprodil, ifosfamide,iguratimod, ilaprazole, ilomastat, iloperidone, iloprost trometamol,ILX23-7553, imatinib, imidapril, imidazole salicylate, imipenem,imipramine, imipramine N-Oxide, imiquimod, imolamine, implitapide,improsulfan, inactivated, inaperisone, incadronate, incadronic acid,indalpine, indanazoline, indapamide, indecainid, indeloxazine,indeloxazine, indenolol, indinavir, indiplon, indisetron, indisulam,indobufen, indocyanine green, indometacin, indoprofen, indoramin,induclem, infliximab, inhibitor, inhibitors, inosine pranobex, inositol,inositol niacinate, inverse agonist Mer, iobenguane, iobenzamic acid,iobitridol, iocarmic acid, iocetamic acid, iodamide, iodide, iodine,iodipamide, iodixanol, iodoalphionic acid, iodochlorhydroxyquin,iodoform, iodopyracet, iodopyrrole, iodoquinol, iodosubgallate,iofetamine 1231, ioglycamic acid, iohexol, iomeglamic acid, iomeprol,iopamidol, iopanoic acid, iopentol, iophendylate, iophenoxic acid,iopromide, iopronic acid, iopydol, iopydone, iothalamic acid, iotrolan,ioversol, ioxaglic acid, ioxilan, IP-751, ipidacrine, IPL-576092,ipodate, iponiazid, ipratpopium, ipratropium, ipratropium bromide,iprazochrome, ipriflavone, iprindole, iproclozid, ipsapiron, irbesartan,IRFI-042, IRFI-165, iridomyrmecin, irindalone, irinotecan, irofulven,iron sorbitex, irsogladine, IS-741, isaglitazone, ISAtx-247, isbogrel,isepamicin, isoaminile, isobutyl p-aminobenzoate, isoconazole,isoetharine, isofloxythepin, isoflurane, isoflurophate, isoladol,isomethadone, isometheptene, isoniazid, isonixin, isopromethazine,isopropamide iodide, isopropyl alcohol, isopropyl unoprostone,isoproterenol, isosorbide, isosorbide dinitrate, isosorbide mononitrate,isothipendyl, isotretinoin, isovaleryl, isoxepac, isoxicam, isoxsuprine,isradipine, israpafant, ISV-403, itasetron, ITF-282, itopride,itraconazole, itramin, itriglumide, iturelix, ivabradine, ixabepilone,J-104132, J-107088, J-113397, Janex-1, josamycin, JTV-519, K-777, kainicacid, kalimate, kallidin, KB-130015, KCB-328, kebuzone, ketamine,ketanserin, ketazolam, kethoxal, ketobemidone, ketoconazole, ketoprofen,ketorolac, ketorolac, ketotifen, khellin, kinetin, KNI-272, KP-103,KP-157, KP-544, KRN-5500, KT-136, KUL-7211, KW-2170, KW-6002, KW-7158,L-365260, L-5-hydroxy-tryptophan, L-745337, L-758298, L-826141,labetalol, lacidipine, lactic acid, lactitol, lactulose, lafutidine,lamifiban, lamivudine, lamotrigine, landiolol, lanicemine, laniquidar,lanoconazole, lanoteplase, lanreotide, lansoprazole, lanthanumcarbonate, lapatinib, laquinimod, lasofoxifene, latamoxef, latanoprost,lauroguadine, laurolinium acetate, lawsone, LAX-111, lazabemide,LB-30057, L-cysteine, lefetamine, leflunomide, leflunomide, leiopyrrole,lenampicillin, lentinan, lepirudin, lercanidipine, lerisetron,lesopitron, leteprinim, letosteine, letrozole, leucocyanidin,leuprolide, leuprolide acetate, leuprorelin, levallorphan, levaminsole,levcromakalim, levetiracetam, levobetaxolol, levobunolol,levobupivacaine, levocabastine, levocetirizine, levodopa,levodropropizine, levofloxacin, levomethadyl acetate, levomoprolol,levonorgestrel, levophacetoperane, levopropoxyphene, levorphanol,levosimendan, levosulpride, levothyroxine, levovirin, lexidronam,lexipafant, LF-15-0195, LF-16-0687, LGD-1550, LH, LH-RH, liarozote,licofelone, licostinel, lidadronate, lidamidine, lidocaine, lidofenin,lidoflazine, limaprost, lincomycin, lindan, linezolid, linoleic acid,linolenic acid, liothyronine, lipase, lipo-dexamethasone,lipo-flurbiprofen, Lipogel HA, LiquiVent, liranaftate, lisinopril,lisofyllin, lisuride, lithium, lithium citrate, lixivaptan, LJP-1082,LLUAlpha, LMP-160, LMP-420, loanzapine, lobaplatin, lobeline,lobenzarit, lodoxamide, lofentanil, lofepramine, lofexidine,loflucarban, lomefloxacin, lomerizine, lomifylline, lomustine,lonafarnib, lonapalene, lonazolac, lonidamine, loperamide, loperamideoxide, loprazolam, loprinone, loracarbef, loraj mine, loratadine,lorazepam, lorcainide, lormetazepam, lornoxicam, losartan, loteprednol,lotrafiban, lovastatin, loxapine, loxiglumide, loxoprofen, Lu-35-138,lubeluzole, lubiprostone, lucanthone, lucanthone, lumefantrine,lumiracoxib, lurtotecan, lutetium texaphyrin, LV-216, LX-104, LY-156735,LY-293111, LY-293558, LY-355703, lyapolate, lymecycline, lynestrenol,lypressin, lysine acetylsalicylate, lysine salicylate,lysophospholipids, M-40403, mabuprofen, mabuterol, macrophagecolony-stimulating factor, MADU, mafenide, mafosfamide, magaldrate,magenta I, magnesium, magnesium carbonate, magnesium chloride, magnesiumcitrate, magnesium gluconate, magnesium lactate, magnesium salicylate,malathion, malotilate, mandelic acid, mandelic acid isoamyl,mangafodipir, manidipine, mannomustine, mannose-6-phosphate,maprotilline, maribavir, marimastat, maxacalcitol, mazindol,mazipredone, MC-5723, MCC-478, MCI-154, m-cresyl acetate, MDAM, MDI-101,MDI-403, MDL-100907, mebendazole, mebeverine, mebhydroline, mebrofenin,mebutamate, mecamylamine, mechlorethamine, mechlorethamine oxide,mecillinam, meclizine, meclocycline, meclofenamate, meclofenamic acid,meclofenoxate, mecloqualone, mecysteine, medazepam, medifoxamine,medrogestone, medronic acid, medroxyprogesterone, medrysone, mefenamicacid, mefenorex, mefexamide, mefloquine, mefruside, megestrol, meglumin,meglutol, melagatran, melanocortin-4 agonist, melarsoprol, melengestrol,melevodopa, melinamide, melitracen, meloxicam, melperone, melphalan,meluadrine, memantine, MEN-10700, MEN-10755, menadiol, menadione,menadoxime, menbutone, menogaril, MENT, menthol, menthyl valerate,meobentine, meparfynol, mepartricin, mepazine, mepenzolate bromide,meperidine, mephenesin, mephenoxalone, mephentermine, mephenytoin,mephobarbital, mepindolol, mepitiostane, mepivacaine, mepixanox,mepredni sone, meprobamate, meproscillarin, meptazinol, mequitazine,meralein, meralluride, merbromin, mercaptomerin, mercumallylic acid,mercuric oleate, mercuric oxycyanide, merimepodib, meropenem, mersalyl,mertiatide, mesalamine, mesalazine, mesna, mesoridazine, mestanolone,mesterolone, mestranol, mesulfen, metaclazepam, metampicillin,metapramine, metaproterenol, metaraminol, metazocine, metergoline,metformin, methacholine, methacycline, methadone, methafurylene,methamphetamine, methandriol, methandrostenolone, methantheline,methapyrilene, methaqualone, metharbital, methazolamide, methdilazine,methenamine, methenolone, methestrol, methetoin, methicillin,methimazole, methiodal, methionic acid, methionine, methisazone,methitural, methixene, methocarbamol, methohexital, methotrexate,methotrimeprazine, methoxamine, methoxsalen, methoxycinnamate,methoxyflurane, methoxyphenamine, methoxypromazine, methscopolamine,methsuximide, methyclothiazide, methyl blue, methyl nicotinate, methylpropyl ether, methyl salicylate, methyl tert-butyl ether,methylbenzethonium chloride, methylbromide, methylcobalamin, methyldopa,methylene blue, methylergonovine, methylhexaneamide, methylphenidate,methylprednisolone, methylpredni solone, methylpredni solone,methylthiouracil, methyltrienolone, methyprylon, methysergide,metiazinic acid, metipranolol, metoclopramide, metocurine iodide,metofenazate, metolazone, metopimazine, metopon, metoprolol,metralindole, metrizamide, metrizoic acid, metron s, metyrapone,metyrosine, mexazolam, mexenone, mexiletine, mezlocillin, MFH-244,mianserin, mibefradil, miboplatin, micafungin, miconazole, micronomicin,midaxifyline, midazolam, midecamycin, midecamycin acetate, midesteine,midodrine, midostaurin, mifepristone, miglitol, miglustat, mildronate,milnacipran, miloxacin, milrinone, miltefosine, minaprine, minocycline,minodronic acid, minoxidil, miokamycin, mirtazapine, misoprostol,mitemcinal, mitiglinide, mitobronitol, mitoguazone, mitolactol,mitomycin, mitotane, mitoxantrone, mitoxantrone, MIV-210, mivacurium,mivazerol, mizolastine, mizoribine, MKC-733, MLN-519, MLN-576,moclobemide, modafinil, moexipril, mofarotene, mofebutazone, mofegiline,mofetil, mofezolac, MOL-6131, molindone, molsidomine, mometasone,monatepil, monobenzone, monoethanolamine, monolaurin, monoterpene diols,montelukast, monteplase, moperone, mopidamol, moprolol, moracizine,morazone, moricizine, moroxydine, morphazinami de, morphine,morphine-6-glucuronide, mosapramine, mosapride, motexafin, motretinide,moveltipril, moxalactam, moxastine, moxaverine, moxestrol, moxifloxacin,moxisylyte, moxonidine, M-PGA, MPI-5010, MPI-5020, MPL, MRS-1754,MS-209, MS-275, MS-325, MS-377, mupirocin, muscarin, muzolimine,MX-1013, mycophenolate, mycophenolic acid, myrophine,N-(hydroxymethyl)-nicotinamide, N,N,N′,N′-tetraethylphthalami de,N-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]naphthalene-2-carboxamide,N2-formyl-sulfisomidine, N4-sulfanilylsulfanilamide,N413-D-glucosylsulfanilamide, nabilone, nabumetone, N-acetylcysteine,N-acetylmethionine, nadifloxacin, nadolol, nadoxolol, nafamostat,nafarelin, nafcillin, nafronyl, naftidofuryl, naftifine, naftopidil,nalbuphine, nalidixic acid, nalmefene, nalorphine, naloxone, naltrexone,NAMI, naminidil, nandrolone, napadisilate, naphazoline, naphthalene,naproxen, naproxen betainate, naratriptan, narceine, narcobarbital,natamycin, nateglinide, N-butyldeoxy-nojirimycin, N-butylscopolammoniumBromide, NC-503, NC-531, NCX-1000, NCX-4016, NCX-456, NCX-950,n-docosanol, NE-100, nealbarbital, nebivolol, nebostinel, nebracetam,nedaplatin, nedocromil, nefazodone, nefiracetam, nefopam, negamycin,nelfinavir, nemonapride, neostigmine, nepadutant, neramexane, neridronicacid, neriifolin, N-ethylamphetamine, neticonazole, netilmicin,nevirapine, NGD-98-2, nialamide, niaprazine, nicametate, nicaraven,nicardipine, nicergoline, niceritrol, niclosamide, nicoclonate,nicofuranose, nicomol, nicomorphine, nicorandil, nicotinamide, nicotine,nicotinic acid, nicotinic acid benzyl ester, nicotinyl alcohol,nifedipine, nifekalant, nifenalol, niflumic acid, nifuratel,nifurfoline, nifuroxazide, nifuroxime, nifurpirinol, nifurprazine,nifurtimox, nifurtoinol, nifurzide, NIK-254, nikethamide, nilutamide,nilvadipine, nimesulide, nimetazepam, nimodipine, nimorazole, nimustine,ninopterin, NIP-142, NIP-531, niperotidine, nipradilol, niridazole,nisoldipine, nitazoxanide, nitisinone, nitracrine, nitrazepam,nitrendipine, nitroflurbiprofen, nitrofurantoin, nitrofurazone,nitroglycerin, nitromersol, nitronaproxen, nitroxazepine, nitroxoline,nizatidine, nizofenone, NM-3, NM-702, N-methylephedrine,N-methylepinephrine, N-methylglucamine, NN-414, NNC-05-1869, nobel,nogalamycin, nolatrexed, nolomirole, nolpitantium, nomegestrol,nomifensine, noprylsulfamide, norbolethone, nordazepam, nordefrin,nordihydroguaiaretic acid, norelgestromin, norepinephrine,norethandrolone, norethindrone, norethynodrel, norfenefrine,norfloxacin, norgesterone, norgestimate, norgestrel, norgestrienone,norlevorphanol, normethadone, normethandrone, normorphine, norphenazone,norpipanone, norpseudoephedrine, nortriptyline, norvinisterone,noscapine, novembichin, novobiocin, noxiptillin, noxythiolin, NS-1209,NS-1231, NS-126, NS-220, NS-2330, NS5A inhibitors, NS-7, NS-8,NSC-330507, NSC-619534, NSC-697726, N-sulfanilyl-3,4-xylamide, NU-6027nucleosides, NV-07, NVP-SRA880, NW-1029, NXY-059, Nylidrin, NZ-314,NZ-419, obidoxime chloride, OC-108, ocinaplon, octabenzone, octacaine,octamoxin, octaverine, octenidine, octodrine, octopamine, octotiamine,octreotide, octyl, ofloxacin, oleandrin, oleic acid,olmesartan—medoxomil, o-lodohippurate, olopatadine, olpadronic acid,olsalazine, oltipraz, OM-294DP, omacor, omapatrilat, omeprazole,omiloxetine, omoconazole, onapristone, ondansetron, ONO-3403, ONO-4128,ONO-8815 Ly, ONT-093, OPC-14523, OPC-31260, OPC-51803, OPC-6535,opiniazide, opioid analgesics, opipramol, orazamide, orazipone,Org-12962, Org-24448, oritavancin, orlistat, ormeloxifene, ornidazole,ornipressin, ornithine, ornoprostil, orotic acid, orphenadrine,orthocaine, osalmid, osanetant, osaterone, oseltamivir, OSI-7836,OSI-7904, ospemifene, otilonium bromide, ouabain, oxaceprol, oxacillin,oxaflozane, oxaliplatin, oxalyt-C, oxamarin, oxametacine, oxamniquine,oxandrolone, oxantel, oxapropanium, oxaprozin, oxatomide, oxazepam,oxazolam, oxcarbazepine, oxeladin, oxendolone, oxethazaine, oxetoron,oxiconazole, oxidronic acid, oxiniacic acid, oxiracetam, oxitropium,oxolamin, oxolinix acid, oxophenarsine, oxprenolol, oxybenzone,oxybutynin, oxycinchophen, oxycodone, oxygent, oxymesterone,oxymetazoline, oxymetholone, oxymethurea, oxymorphone, oxypendyl,oxypertine, oxyphenbutazone, oxyphencyclimine, oxyphenisatin,oxyphenonium, oxypinocamphone, oxypurinol, oxytedrine, oxytetracycline,ozagrel, p-(benzyl sulfonamido)-benzoic acid, P-100, P-1202, P32/98,PA-824, PACAP 38, pactitaxel, PADRE, pagoclone, PAI inhibs, palindore,palivizumab, palonosetron, pamabrom, pamaquine, pamicogral, pamidronate,p-aminobenzoic acid, p-aminohippuric acid, p-amino-propiophenone,p-aminosalicylic acid, panavir, pancuronium, panipenem, pantethine,pantoprazole, pantothenic acid, papain, papaverine, paracetamol,paraflutizide, paraldehyde, paramethadione, paramethasone, paranyline,parathyroid hormone, parecoxib, parethoxycaine, pargyline, paricalcitol,paromomycin, paroxetine, paroxypropione, parsalmide, patrin-2,pazinaclone, pazufloxacin, p-bromoacetanilide, PC-NSAIDs, PD-0166285,pecilocin, pefloxacin, pegvisomant, pelletierine, pemetrexed,pemirolast, pemoline, pempidine, PEN-203, penamecillin, penbutolol,penciclovir, penethamate, penfluridol, penicillamine, penicillin G,penicillin G Procaine, penicillin N, penicillin O, penicillin V,penimepicycline, penntuss, pentaerythritol, pentaerythritol,pentaerythritol chloral, pentagastrin, pentagestrone, pentalyte, pentamthonium, pentamidine, pentazocine, pentetate, pentetic acid,pentetreotide, penthienate, pentifyllin, pentigetide, pentisomide,pentobarbital, pentolinium, pentorex, pentosan, pentostatin,pentoxifylline, pentoxyl, pentrinitrol, pentylenetetrazole, peplomycin,peptide, peptide, perazine, perfiromycin, perflubron, perfosfamide,pergolide, perhexiline, pericyazine, perifosine, perillyl alcohol,perimethazine, perindopril, periodyl, perisoxal, perlapine,permanganate, permethrin, perospirone, perphenazine, petroleum benzin,PH-10, phanquinone, pharmacor, pharmaprojects no. 6362, pharmaprojectsno. 4994, pharmaprojects no. 5325, pharmaprojects no. 5972,pharmaprojects no. 6446, pharmaprojects no. 6590, pharmaprojects no.6656, pharmaprojects no. 6691, pharmaprojects no. 6743, pharmaprojectsno. 6748, phenacaine, phenacemide, phenacetin, phenadoxone, phenallymal,phenamet, phenamide, phenazocine, phenazopyridine, phenbutamide,phencyclidine, phendimetrazine, phenelzine, phenesterine,phenetharbital, phenethicillin, pheneturide, phenformin,phenglutarimide, phenindamine, phenindione, pheniprazine, pheniramine,phenmetrazine, phenobarbital, phenobutiodil, phenocoll, phenoctide,phenolphthalein, phenolphthalol, phenol sulfonphthalein,phenol-tetrachlorophthalein, phenoperidine, phenosulfazole,phenoxybenzamine, phenoxypropazine, phenprobamate, phenprocoumon,phenserine, phensuximide, phentermine, phentetiothalein, phentolamine,phenyl acetylsalicylate, phenyl aminosalicylate, phenyl salicylate,phenylbutazone, phenylephrine, phenylethanolamine, phenylmercury,phenylmethylbarbituric acid, phenylpropanolamine,phenylpropyl-methylamine, phenyltoloxamine, phenyramidol, phenytoin,phethenylate, phloroglucinol, pholcodine, pholedrine, phoramide,phosphate, phosphate, phosphocreatine, phosphocysteamine,phosphorylcholine, phthalylsulfathiazole, phthalysulfacetamide,p-hydroxyephedrine, phylloquinone, physostigmine, phytic acid, PI-88,piberaline, piboserod, picilorex, picloxydine, picoperine, picosulfate,picotamide, picumast, pidotimod, pifarnine, piketoprofen, pildralazine,pilocarpine, piloplex, pilsicainide, pimeclone, pimecrolimus,pimefylline, pimilprost, piminodine, pimobendan, pimozide, pinacidil,pinaverium, pinazepam, pindolol, pioglitazone, pipacycline, pipamazine,pipamperone, pipazethate, pipebuzone, pipecurium, pipecuronium,pipemidic acid, pipenzolate bromide, piperacetazine, piperacillin,piperazine adipate, piperidione, piperidolate, piperilate, piperineanalogues, piperocaine, piperonal, piperoxan, piperylone, pipobroman,piposulfan, pipotiazine, pipoxolan, pipradrol, piprozolin, piracetam,pirarubicin, pirazolac, pirbuterol, pirenoxine, pirenzepine, piretanide,pirfenidone, piribedil, piridocaine, pirifibrate, piritramide,piritrexim, pirlindole, pirmenol, piroctone, piroheptine, piromidicacid, piroxicam, piroxicam betadex, piroxicam cinnamate, pirozadil,pirprofen, pitavastatin, pivagabine, pivaloyloxymethyl,pivalylbenzhydrazine, pivampicillin, pivampicillin/pivmecillinam,pivcefalexin, pivmecillinam, pixantrone, pizotifen, pizotyline, PKI-166,p-lactophenetide, plafibride, plasminogen activator, plasmocid,platonin, plaunotol, PLD-118, PLD-147, pleconaril, plicamycin,p-methyldiphenhydramine, PMS-601, Pneumococcal, PNU-288034,podophyllotoxin, polaprezinc, poldine methylsulfate, policresulen,polidexide, polidocanol, poliovirus vaccine, poly-ADPRT inhibitors,polyestradiol, polyphenon E, polythiazide, porfimer, posaconazole,posatirelin, potassium, potassium, potassium, potassium chloride,potassium gluconate, potassium p-aminobenzoate, povidone,povidone-iodine, PP-117, PR-2699, PR-608, practolol, prajmaline,pralidoxime, pralnacasan, pramipexole, pramiracetam, pramiverin,pramlintide, pramoxine, pranidipine, pranlukast, pranoprofen,prasterone, pratosartan, pravastatin, prazepam, praziquantel, prazosin,prednicarbate, prednimustine, prednisolone, prednisolone21-diethylaminoacetate, prednisolone farnesil, prednisolone sodium,prednisone, prednival, prednylidene, pregabalin, pregnan-3α-ol-20-one,premarin+trimegestone, prenalterol, prenoxdiazine, prenylamine,prezatide, pridinol, prifinium, prilocaine, primaquine, primidone,prinomastat, PRO-2000, probenecid, probucol, procainamide, procaine,procarbazine, procaterol, prochlorperazine, procodazol, procyclidine,procymate, prodipine, proflavine, progabide, progesterone,proglumetacin, proglumide, proheptazine, prolactin, prolintane,prolonium, promazine, promedol, promegestone, promestriene,promethazine, pronethalol, propacetamol, propafenone, propagermanium,propallylonal, propamidine, propane-1,2-diol, propanidid, propantheline,proparacaine, propatyl, propenidazole, propentofylline, propicillin,propiomazine, propionic acid, propionyl 1-carnitine, propipocaine,propiram, propiverine, propizepine, propofol, propoxycaine,propoxyphene, propranolol, propylhexedrine, propyliodone,propylthiouracil, propyphenazone, proquazone, proscillaridin,prostacyclin, prostaglandin E1, prostaglandin E2, prostaglandin F2a,prosultiamine, protein C, protheobromine, prothipendyl, protiofate,protionamide, protizinic acid, protoanemonin, protoklol, protoporphyrinIX, protriptyline, pro-urokinase, proxazole, proxetil, proxibarbal,proxigermanium, proxyphylline, prozapine, prucalopride, prulifloxacin,pseudococaine, pseudoephedrine, pseudoephedrine,pseudoephedrine+triprolidine, psilocybin, PSK-3841,p-sulfanilyl-benzylamine, PT-141, pteropterin, puromycin, PX-12,pyrantel, pyrazinamide, pyridinol carbamate, pyridostigmine, pyridoxal5-phosphate, pyridoxine, pyrilamine, pyrimethamine, pyrinoline,pyrisuccideanol, pyrithione, pyrithyldione, pyritinol, pyrocatechol,pyrogallol, pyronaridine, pyrophosphate, pyrovalerone, pyroxylin,pyrrobutamine, pyrrocaine, pyrrolntrin, pyrvinium pamoate, quazepam,quercetin, quetiapine, quinacillin, quinacrine, quinagolide, quinapril,quinaprilat, quinapyramine, quinbolone, quinestradiol, quinestrol,quinethazone, quinfamide, quinidine, quinine, quinocide, quinupramine,quinupristin, R-107500, R-667, rabeprazole, racecadotril,racemethorphan, raloxifene, raltitrexed, ramatroban, ramifenazone,ramipril, ramosetron, Ramot project No. 1097, ranimustine, ranitidine,ranitidine bismuth, ranolazine, ranpirnase, rapacuronium, rasagiline,raubasine, ravuconazole, raxofelast, razoxane, RC-529, rebamipide,rebimastat, reboxetime, remacemide, remifentanil, reminetant,remoxipride, renzapride, repaglinide, repertaxin L-lysine salt,repinotan, repirinast, reposal, reproterol, rescimetol, rescinnamine,reserpiline, reserpine, resibufogenin, resiquimod, resorcinol,reteplase, retigabine, retinoic acid, revimid, R-flurbiprofen, rho (D)immune, rho-kinase inhibitors, ribavirin, riboflavin, ribostamycin,ricinoleic acid, ridogrel, rifabutin, rifalazil, rifametane, rifamide,rifampicin+trimethoprim, rifampin, rifamycin SV, rifapentine, rifaximin,rifaximine cream, rilmazafone, rilmenidine, riluzole, rimantadine,rimazolium, rimexolone, rimiterol, rimonabant, riodoxol, rioprostil,risedronate, risedronic acid, risperidone, ritanserin, ritipenem,ritodrine, ritonavir, rituximab, rivastigmine, rizatriptan, RJR-2403,RNA Stealth, Ro-0094889, Ro-61-1790, rociverine, rocuronium, rofecoxib,roflumilast, rokitamycin, rolipram, rolitetracycline, romurtide,ronifibrate, ropinirole, ropivacaine, roquinimex, rosaprostol,rosaramicin, rose bengal, rosiglitazone, rosoxacin, rostaporfin,rosuvastatin, rotigotine, rotraxate, roxarsone, roxatidine, roxifiban,roxindol, roxithromycin, RPR-109881A, RPR-130401, R-roscovitine,RS-0406, RSR-13, rubijervine, rubitecan, ruboxistaurin, rufinamide,rufloxacin, rupatadine, rutin, RWJ-54428, S-0139, S-15535, S-18886,S-34730, S-3578, 5-36496, S-36527, S-5751, S-8510, S-8921, sabcomeline,sabeluzole, S-adenosylmethionine, safinamide, salacetamide,salazosulfadimidine, salbutamol, salicin, salicyl alcohol, salicylamide,salicylamide 0-acetic acid, salicylanilide, salicylic acid,salicylsilfuric acid, salinazid, salmeterol, salsalate, salverine,samarium ¹⁵³Sm, sampatrilat, sancycline, saperconazole, sapropterin,saquinavir, saralasin, saredutant, saredutant, sarizotan, sarizotan,sarpogrelate, sarpogrelate, satigrel, satigrel, satraplatin,satraplatin, satumomab, satumomab, SB-237376, SB-237376, SB-238039,SB-238039, SB-277011, SB-277011, scarlet red, SCH-00013, SCH-00013,Sch-23863, Sch-23863, Sch-57790, Sch-63390, scillarenin, scopolamine,scopolamine, scopolamine N-oxide, SCS technology, secalciferol,secnidazole, secobarbital, selegiline, selenomethionine, sematilide,semotiadil, seocalcitol, sepimostat, seratrodast, sertaconazole,sertaconazole, sertindole, sertindole, sertraline, sertraline,sestamibi, setastine, setastine, sevelamer, sevelamer, sevoflurane,sevoflurane, SG-210, sibutramine, siccanin, sildenafil, silodosin,silprostone, silver lactate, silver picrate, silver sulfadiazine,simetride, simfibrate, simvastatin, sincalide, sintropium bromide,sisomicin, sitafloxacin, sitamaquine, sitaxsentan, sivelestat, SJA-6017,SL-65-1498, SLV-306, SLV-308, Sm153 lexidronam, S-methylmethionine,SMP-300, SN-38, SNAP-7941, SOA-132, soblidotin, sobrerol, sobuzoxane,sodium arsanilate, sodium arsphenamine, sodium chloride, sodiumdibunate, sodium folate, sodium formaldehydesulfoxylate, sodiumhyaluronate, sodium iodomethamate, sodium nitrite, sodium nitroprusside,sodium oxybate, sodium phenol-sulfonate, sodium phenylbutyrate, sodiumphosphate, sodium prasterone sulfate, sodium propionate, sodiumsalicylate, sodium tetradecyl sulfate, sofalcone, solasulfone,solifenacin, sorbinicate, sorbitol, sorivudine, sotalol, soterenol,sozoiodolic acid, spaglumic acid, sparfloxacin, sparteine, SPA-S-843,spasmolytol, SPD-754, spectinomycin, SPI-339, spiperone, spirapril,spirogermanium, spironolactone, SR-121463, SR-144190, SR-146131,SR-271425, SR-27897, SR-31747, SR-58611, SS732, SS-750, SSR-149415,SSR-180575, SSR-181507, SSR-591813, SST-101, SSY-726, ST-200,stachyfilin, stallimycin, stampidine, stannous, stannsoporfin,stanolone, stanozolol, staph aureus ther, STAT4 inhibitors, stavudine,stenbolone, stepronim, stibocaptate, stibophen, stilbamidine,stiripentol, streptodornase, streptomycin, streptonicozid,streptonigrin, streptozocin, strontium ranelate, strontium-89 chloride,succimer, succinimide, succinylcholine, succinylcholine,succinylsulfathiazole, succisulfone, suclofenide, sucralfate,sufentanil, sulbactam, sulbactam+ampicillin, sulbenicillin, sulbentine,sulbutiamine, sulconazole, suleptanate, sulesomab, sulfabenzamide,sulfacetamide, sulfachlorpyridazine, sulfachrysoidine, sulfacytine,sulfadiazine, sulfadicramide, sulfadimethoxine, sulfadoxine,sulfaethidole, sulfaguanidine, sulfaguanole, sulfalene, sulfaloxic acid,sulfamerazine, sulfameter, sulfamethazine, sulfamethizole,sulfamethomidine, sulfamethoxazole, sulfamethoxypyrazine,sulfamethoxypyridazine, sulfametrole, sulfamidochrysoidine, sulfamoxole,sulfanilamide, sulfanilic acid, sulfanilylurea, sulfaperine,sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine,sulfarside, sulfarsphenamine, sulfasalazine, sulfasomizole,sulfasymazine, sulfathiazole, sulfathiourea, sulfinalol, sulfinpyrazone,sulfiram, sulfisomidine, sulfisoxazole, sulfobromophthalein,sulfonethylmethane, sulfoniazide, sulfonic acid, sulfonmethane,sulforidazine, sulfoxone, sulindac, sulisatin, sulisobenzone, sulmarin,sulmazole, suloctidil, sulphan blue, sulpiride, sultamicillin,sulthiame, sultopride, sultosilic acid, sumanirole, sumatriptan,SUN-N8075, suplatast, suprofen, suramin, surfactant TA, suriclone,suxibuzone, SYM-1010, SYM-2081, SYM-2207, symclosene, Syn-1253,Syn-2190, Syn-2869, synephrine, syrosingopine, T-1095, T-1249, T-3912,T-588, T-67, T-82, TA-2005, TA-2005, TA-993, tabimorelin, tacalcitol,tacedinaline, tacrine, tacrolimus, tadalafil, tafenoquine, tafluposide,TAK-375, TAK-427, TAK-559, taka-diastase, talampanel, talampicillin,talaporfin, talastine, talbutal, talinolol, talipexole, talnetant,talniflumate, taltirelin, tamoxifen, tamsulosin, tandospirone,tannoform, taprostene, tariquidar, TAS-103, tasosartan, taurocholicacid, taurolidine, tazanolast, tazarotene, tazobactam,tazobactam+piperacillin, TBC-3711, TCH-346, tebipenem, teboroxime,tecadenoson, tecastemizole, Technetium ⁹⁹Tc, teclothiazide, teclozan,tedisamil, teflurane, tegafur, tegafur+uracil, tegaserod, teicoplanin,telbivudine, telenzepine, telithromycin, telmesteine, telmisartan,telomerase inhibs, temazepam, temiverine, temocapril, temocillin,temoporfin, temozolomide, tenatoprazole, tenecteplase, tenidap,teniposide, tenofovir, tenofovir disoproxil, tenonitrozole, tenoxicam,tenuazonic acid, teprenone, terazosin, terbinafine, terbutaline,terconazole, terfenadine, terguride, terlipressin, terodiline,terofenamate, terpin, tertalolol, tert-pentyl alcohol, tesaglitazar,tesmilifene, testolactone, testosterone, tetrabamate, tetrabarbital,tetrabenazine, tetracaine, tetrachloroethylene, tetracine, tetracycline,tetrahydrozoline, tetrandrine, tetrantoin, tetrazepam, tetrofosmin,tetroxoprim, Tevenel tezacitabine, tezosentan, thalidomide, thenaldine,thenyldiamine, theobromine, theofibrate, theophylline, thiabendazole,thiacetazone, thiacymserine, thialbarbital, thiamine, thiamiprine,thiamphenicol, thiamylal, thiazesim, thiazinamium, thiazolinobutazone,thiazolsulfone, thibenzazoline, thiemalat, thiethylperazine,thimerfonate, thimerosal, thiobarbital, thiobutabarbital,thiocarbamizine, thiocarbarsone, thiocolchicine, thiocresol, thiocticacid, thioglycerol, thioguanine, thioimrag, thiopental,thiophosphoramide, thiopropazate, thioproperazine, thioridazine,thiosulfate, thiothixene, thiovir, thiphenamil, thiram, thonzylamine,thozalinone, thromboplastin, thurfyl nicotinate, thymectacin, thymol,thymopentin, thymyl N-isoamylcarbamate, thyropropic acid, thyroxine,tiadenol, tiagabine, tiamenidine, tianeptine, tiapride, tiaprofenicacid, tiaramide, tiazofurin, tibezonium, tibolone, ticarcillin,ticlopidine, ticrynafen, tiemonium, tigecycline, tigemonam, tigloidine,tilidine, tilisolol, tilmacoxib, tiludronic acid, timentin, timepidium,timiperone, timolol, timonacic, tin ethyl etiopurpurin, tinazoline,tinidazole, tinoridine, tiocarlide, tioclomarol, tioconazole, tiopronin,tiotropium, tioxolone, tipepidine, tipifarnib, tipranavir, tiquizium,tirapazamine, tiratricol, tirilazad, tirofiban, tiropramide, titaniumsulfate, tiuxetan, tixocortol, tizanidine, TLK-199, TLK-286, TNF-βanalogue, TNP-470, TO-186, tobramycin, tocainide, tocamphyl,tocladesine, tocoretinate, todralazine, tofenacin, tofimilast,tofisopam, tolazamid, tolazolin, tolbutamide, tolcapone, tolciclate,tolcyclamide, tolevamer, tolfenamic acid, tolindate, toliprolol,tolmetin, tolnaftate, tolonidine, tolonium, toloxatone, tolperisone,tolpropamine, tolrestat, tolserine, tolterodine, tolvaptan, tolycaine,topiramate, topoisomerase, topotecan, torasemide, torcetapib,torcitabine, toremifene, torsemide, tositumomab, tosulfloxacin,tramadol, tramazoline, trandolapril, tranexamic acid, tranilast,trans-retinoic acid, tranylcypromine, trapidil, trastuzumab, travoprost,traxanox, traxoprodil, trazodone, tremacamra, trenbolone, trengestone,treosulfan, trepibutone, treprostinol, tretinoin, tretoquinol, TRH,TRI-50b, triacetin, triamcinolone, triamcinolone, triamcinolone,triamcinolone acetonide, triamterene, triapine, triaziquone, triazolam,tribenoside, tribromophenate, trichlorfon, trichlormethiazide,trichlormethine, trichloroethylene, triclobisonium, triclocarban,triclofenol piperazine, triclofos, triclosan, tricromyl, tridihexethyliodide, trientine, triethanolamine, triethylenemelamine,trifluoperazine, trifluperidol, triflupromazine, trifluridine,triflusal, triflutate, trihexyphenidyl, trimazosin, trimebutine,trimecaine, trimeprazine, trimetazidine, trimethadione, trimethaphan,trimethobenzamide, trimethoprim, trimetozine, trimetrexate,trimipramine, trimoprostil, triolstane, trioxsalen, tripamide,triparanol, tripelennamine, triprolidine, triptorelin, tritiozine,tritoqualine, TRK-530, TRK-820, troclosene, trofosfamide, troglitazone,troleandomycin, trolnitrate, tromantadine, trometamol, trometamol,tromethamine, tromethamine, tropacine, tropesin, tropicamide, tropine,tropisetron, trospectomycin, trospium, trovafloxacin, troxacitabine,troxerutin, troxipide, trypan red, tryparsamide, tryptophan, TSH,TSN-09, TU-2100, tuaminoheptane, tubercidin, tubocurarine chloride,tulobuterol, TV-3326, TY-11223, TY-12533, TYB-3215, tybamate, tyloxapol,tymazoline, tyramine, tyropanoate, ubenimex, ufenamate, undecylenicacid, unoprostone, UR-8880, uracil mustard, uralyt-U, urapidil, urea,uredepa, urethan, uridine 5′-triphosphate, urinastatin, ursodeoxycholicacid, ursodiol, ushercell, uzarin, vaccine, Diphtheria Vaccine,Polyvalent Vaccine, valacyclovir, valdecoxib, valdetamide, valethamate,valganciclovir, valnoctamide, valomaciclovir, valproate, valproic acid,valpromide, valrocemide, valrubicin, valsartan, valspodar, vardenafil,varespladib, varicella virus, vatanidipine, VEA, vecuronium, velnacrine,venlafaxine, veralipride, verapamil, verteporfin, vesnarinone,vetrabutine, VF-233, VI-0134, vidarabine, vigabatrin, vilazodone,viloxazine, viminol, vinbarbital, vinblastine, vinburnine, vincamine,vinconate, vincristine, vindesine, vinflunine, vinorelbine, vinpocetine,vinyl ether, vinylbital, viquidil, viridin, visnadine, vitamin A,vitamin B12, vitamin C, vitamin D2, vitamin D3, vitamin K5, prenatalvitamins, VLA-4 antagonists, VNP-4010M, voglibose, voriconazole,vorozole, VUF-K-8788, warfarin, WF-10, WMC-79, wound healing matrix,WP-170, xaliproden, xamoterol, xanomeline, xanthinol niacinate,xemilofiban, xenbucin, xibenolol, xibornol, ximelagatran, ximoprofen,xipamide, xorphanol, XR-5118, XR-5944, xylometazoline, xylose, YH-1885,YM-511, YM-598, yohimbine, YT-146, Z-321, Z-335, zafirlukast,zalcitabine, zaldaride, zaleplon, zaltoprofen, zanamivir, zanapezil,zatebradine, ZD-0473, ZD-0947, ZD-6126, ZD-9331, zebularine, zelandopam,zenarestat, ziconotide, zidovudine, zileuton, zimeldine, zinc acetate,zinc acexamate, zinc ibuprofenate, zinc p-phenolsulfonate, zincsalicylate, zinostatin, zinostatin stimalamer, zipeprol, ziprasidone,zofenopril, zofenpril+HCTZ, zoledronic acid, zolimidine, zolmitriptan,zolpidem, zomepirac, zonampanel, zoniporide, zonisamide, zopiclone,zopolrestat, zorubicin, zosuquidar, zotepine, ZP-123, Z-tamoxifen,zuclopenthixol, α1-antitrypsin, α-bisabolol, α-chloralose, α-ethylbenzylalcohol, α-glucose-1-phosphate, α-phenylbutyramide, α-santonin,α-terpineol, α-tocopherol, β-alethine, β-benzalbutyramide, β-carotene,β-eucaine, β-propiolactone, β-sitosterol, γ-aminobutyric acid,γ-hydroxybutyrate, γ-linolenic acid, δ-aminolevulinic acid,ε-acetamidocaproic, and ε-aminocaproic acid. See also U.S. Pat. No.7,927,613, which is incorporated herein by reference in its entirety.Other pharmaceutically acceptable coformers include those delineated inthe “Generally Regarded as Safe” (“GRAS”) and/or the US FDA “EverythingAdded to Food in the United States” (“EAFUS”) lists.

In some of these embodiments, at least one of the one or morepharmaceutically acceptable coformers can be a compound having any oneof formulas (I), (XVIII)-(XXV), and XXVII, (e.g., formula XXIV or XXV)as described in U.S. Pat. No. 10,292,951 which is incorporated herein byreference in its entirety; or any one of the compounds delineated above.In certain of these embodiments, at least one of the one or morepharmaceutically acceptable coformers can be a niclosamide analoguehaving any one of formulas (I), (XVIII)-(XXV), and XXVII (e.g., formulaXXIV or XXV; or XXVI) as described in U.S. Pat. No. 10,292,951 which isincorporated herein by reference in its entirety; or any one of thecompounds specifically delineated above.

In some embodiments, the coformer can be any one or more additionaltherapeutic agents as described herein.

Non-Limiting Combinations

In some embodiments, the cocrystal includes (i) niclosamide; and (ii) apharmaceutically acceptable salt of niclosamide; or a pharmaceuticallyacceptable salt and/or hydrate of niclosamide of a niclosamide analog.

In some embodiments, the cocrystal includes (i) niclosamide; and (ii) asecond API.

In some embodiments, the cocrystal includes (i) a pharmaceuticallyacceptable salt of niclosamide; and (ii) a second API.

In some embodiments, the cocrystal includes (i) niclosamide; and (ii) asecond API.

In some embodiments, the cocrystal includes (i) a pharmaceuticallyacceptable salt of niclosamide; and (ii) an amino acid (e.g., proline,e.g., D-proline, or L-proline, or racemic proline).

In some embodiments, the cocrystal includes (i) niclosamide; and (ii) anamino acid (e.g., proline, e.g., D-proline, or L-proline, or racemicproline).

In some embodiments, the cocrystal includes (i) a pharmaceuticallyacceptable salt of niclosamide; and (ii) a 5-10 (e.g., 5-9, 5-6, or 5)membered heteroaryl, e.g., a nitrogen-containing heteroaryl, e.g.,imidazole.

In some embodiments, the cocrystal includes (i) niclosamide; and (ii) a5-10 (e.g., 5-9, 5-6, or 5) membered heteroaryl, e.g., anitrogen-containing heteroaryl, e.g., imidazole.

For examples, see Sanphui, P. Cryst. Growth Des. 2012, 12, 4588;Imramovsky, A. Crystals 2012, 2, 349-361; and Grifasi, F. Cryst. GrowthDes. 2015, 15, 4588.

Niclosamide Compound of the Co-Crystal

In some embodiments, the chemical purity of the niclosamide compound canbe as defined anywhere herein.

Particle Size of the Co-Crystal

In some embodiments, the co-crystal can have a reduced particle size asdefined anywhere herein for the niclosamide compounds.

In some embodiments, co-crystals having reduced particle size can beprepared by jet milling, e.g., using CMTI equipment NGMP-Mill-A, a2-inch, pancake micronizer manufactured by Sturtevant.

Particle Size Distribution (PSD) can be determined by laser diffractiontechnique, e.g., using a “MALVERN MASTERSIZER 2000” (standard rangebetween 0.020 and 2000.0 microns), model “APA 2000”, equipped with“Hydro 2000 sm” as dispersing unit.

In some embodiments, the co-crystal has a reduced particle size range.

In some embodiments, co-crystal has a particle size range of from about0.1 μm to about 30 μm. In certain embodiments, the co-crystal has aparticle size range of from about 0.1 μm to about 20 μm. In certainembodiments, the co-crystal has a particle size range of from about 0.1μm to about 10 μm.

In some embodiments, the co-crystal has a particle size distributionD(0.9) of from about 1.0 μm to about 15.0 μm. In certain embodiments,the co-crystal has a particle size distribution D(0.9) of from about 1.0μm to about 10.0 μm. In certain embodiments, the co-crystal has aparticle size distribution D(0.9) of from about 6.0 μm to about 8.0 μm.In certain embodiments, the co-crystal has a particle size distributionD(0.9) of from about 2.2 μm to about 3.2 μm.

In some embodiments, the co-crystal has a particle size distributionD(0.1) of from about 0.1 μm to about 1.5 μm. In certain embodiments, theco-crystal has a particle size distribution D(0.1) of from about 0.1 μmto about 1.0 μm. In certain embodiments, the co-crystal has a particlesize distribution D(0.1) of from about 0.3 μm to about 0.9 μm.

In some embodiments, the co-crystal has a particle size distributionD(0.5) of from about 0.5 μm to about 6.0 μm. In certain embodiments, theco-crystal has a particle size distribution D(0.5) of from about 1.0 μmto about 4.0 μm. In certain embodiments, the co-crystal has a particlesize distribution D(0.5) of from about 1.0 μm to about 2.0 μm. Incertain embodiments, the co-crystal has a particle size distributionD(0.5) of from about 2.5 μm to about 3.5 μm.

In some embodiments, the co-crystal has a particle size distributionD(0.9) of from about 1.0 μm to about 10.0 μm, a particle sizedistribution D(0.5) of from about 1.0 μm to about 4.0 μm, and a particlesize distribution D(0.1) of from about 0.1 μm to about 1.0 μm.

In some embodiments, the co-crystal has a particle size distributionD(0.9) of from about 6.0 μm to about 8.0 μm, a particle sizedistribution D(0.5) of from about 1.0 μm to about 4.0 μm, and a particlesize distribution D(0.1) of from about 0.3 μm to about 0.9 μm.

In some embodiments, the co-crystal has a particle size distributionD(0.9) of from about 2.2 μm to about 3.2 μm, a particle sizedistribution D(0.5) of from about 1.0 μm to about 4.0 μm, and a particlesize distribution D(0.1) of from about 0.3 μm to about 0.9 μm.

In some embodiments, the niclosamide compound has a chemical purity ofgreater than about 99.0%; and the co-crystal has a particle sizedistribution D(0.9) of from about 1.0 μm to about 10.0 μm, a particlesize distribution D(0.5) of from about 1.0 μm to about 4.0 μm, and aparticle size distribution D(0.1) of from about 0.1 μm to about 1.0 μm.

In some embodiments, the niclosamide compound has a chemical purity ofgreater than about 99.0%; and the co-crystal has a particle sizedistribution D(0.9) of from about 6.0 μm to about 8.0 μm, a particlesize distribution D(0.5) of from about 1.0 μm to about 4.0 μm, and aparticle size distribution D(0.1) of from about 0.3 μm to about 0.9 μm.

In some embodiments, the niclosamide compound has a chemical purity ofgreater than about 99.0%; and the co-crystal has a particle sizedistribution D(0.9) of from about 2.2 μm to about 3.2 μm, a particlesize distribution D(0.5) of from about 1.0 μm to about 4.0 μm, and aparticle size distribution D(0.1) of from about 0.3 μm to about 0.9 μm.

In some embodiments, the niclosamide compound has a chemical purity ofgreater than about 99.0%; and the co-crystal has a particle size rangeof from about 0.1 μm to about 30 μm, a particle size distribution D(0.9)of from about 1.0 μm to about 10.0 μm, a particle size distributionD(0.5) of from about 1.0 μm to about 4.0 μm, and a particle sizedistribution D(0.1) of from about 0.1 μm to about 1.0 μm.

In some embodiments, the niclosamide compound has a chemical purity ofgreater than about 99.0%; and the co-crystal has a particle size rangeof from about 0.1 μm to about 30 μm, a particle size distribution D(0.9)of from about 6.0 μm to about 8.0 μm, a particle size distributionD(0.5) of from about 1.0 μm to about 4.0 μm, and a particle sizedistribution D(0.1) of from about 0.3 μm to about 0.9 μm.

In some embodiments, the niclosamide compound has a chemical purity ofgreater than about 99.0%; and the co-crystal has a particle size rangeof from about 0.1 μm to about 30 μm, a particle size distribution D(0.9)of from about 2.2 μm to about 3.2 μm, a particle size distributionD(0.5) of from about 1.0 μm to about 4.0 μm, and a particle sizedistribution D(0.1) of from about 0.3 μm to about 0.9 μm.

In certain of the foregoing embodiments, the co-crystal has a particlesize distribution D(0.5) of from about 2.5 μm to about 3.5 μm.

In certain other of the foregoing embodiments, the co-crystal has aparticle size distribution D(0.5) of from about 1.0 μm to about 2.0 μm.

Pharmaceutical Compositions and Administration

General

A niclosamide compound, or a pharmaceutically acceptable salt and/orcocrystal thereof; e.g., a compound, such as niclosamide, or apharmaceutically acceptable salt and/or cocrystal thereof) isadministered to a subject in need thereof by any route which makes thecompound bioavailable (e.g., locally bioavailable). In certainembodiments, the route is respiratory administration.

In some embodiments, a niclosamide compound, or a pharmaceuticallyacceptable salt and/or cocrystal thereof; e.g., a compound, such asniclosamide, or a pharmaceutically acceptable salt and/or cocrystalthereof) is administered as a pharmaceutical composition that includesthe chemical entity and one or more pharmaceutically acceptableexcipients, and optionally one or more other therapeutic agents asdescribed herein.

In some embodiments, the niclosamide compounds can be administered incombination with one or more conventional pharmaceutical excipients.Pharmaceutically acceptable excipients include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifyingdrug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol1000 succinate, surfactants used in pharmaceutical dosage forms such asTweens, poloxamers or other similar polymeric delivery matrices, serumproteins, such as human serum albumin, buffer substances such asphosphates, tris, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethyl cellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, andwool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives canalso be used to enhance delivery of compounds described herein. Dosageforms or compositions containing a chemical entity as described hereinin the range of 0.005% to 100% with the balance made up from non-toxicexcipient may be prepared. The contemplated compositions may contain0.001%-100% of a chemical entity provided herein, in one embodiment0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%.Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington: TheScience and Practice of Pharmacy, 22^(nd) Edition (Pharmaceutical Press,London, U K. 2012).

In some embodiments, the niclosamide compounds described herein or apharmaceutical composition thereof can be administered to subject inneed thereof by any accepted route of administration. Acceptable routesof administration include, but are not limited to, buccal, cutaneous,endocervical, endosinusial, endotracheal, enteral, epidural,interstitial, intra-abdominal, intra-arterial, intrabronchial,intrabursal, intracerebral, intracisternal, intracoronary, intradermal,intraductal, intraduodenal, intradural, intraepidermal, intraesophageal,intragastric, intragingival, intraileal, intralymphatic, intramedullary,intrameningeal, intramuscular, intraovarian, intraperitoneal,intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial,intratesticular, intrathecal, intratubular, intratumor, intrauterine,intravascular, intravenous, nasal, nasogastric, oral, parenteral,percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous,sublingual, submucosal, topical, transdermal, transmucosal,transtracheal, ureteral, urethral and vaginal.

Local Administration

In some embodiments, the niclosamide compounds described herein or apharmaceutical composition thereof are suitable for localadministration, e.g., local administration by way of administering theniclosamide compounds or composition thereof at a particular treatmentsite, (e.g., the respiratory tract, e.g., the upper respiratory tract(e.g., nose or nasal passage) or lower respiratory tract (e.g., lungs);e.g., the digestive tract, the gastrointestinal (“GI”) tract, e.g.,colon; e.g., eye, e.g., skin) so as to provide local administration ofthe chemical entity to the area in need of treatment (e.g., respiratorytract (e.g., nasal passage or the lungs) or the digestive tract (e.g.,colon); eye, skin). In certain embodiments, relatively low systemicexposure of the niclosamide compounds occurs during said localadministration. Examples of such compositions include, e.g.,compositions suitable for administration by inhalation.

In some embodiments, the niclosamide compound described herein or apharmaceutical composition thereof are suitable for local administrationto the respiratory tract, e.g., the upper respiratory tract (e.g., noseor nasal passage) or lower respiratory tract (e.g., lungs). In certainembodiments, upon administration, the local concentration of theniclosamide compound in the respiratory tract is higher (e.g., fromabout 2 times higher to about 1,000 times higher; from about 2 timeshigher to about 900 times higher; from about 2 times higher to about 800times higher; from about 2 times higher to about 700 times higher; fromabout 2 times higher to about 500 times higher; from about 2 timeshigher to about 400 times higher; from about 2 times higher to about 300times higher; from about 2 times higher to about 200 times higher; fromabout 2 times higher to about 100 times higher; from about 2 timeshigher to about 50 times higher, from about 5 times higher to about1,000 times higher; from about 5 times higher to about 900 times higher;from about 5 times higher to about 800 times higher; from about 2 timeshigher to about 700 times higher; from about 5 times higher to about 500times higher; from about 5 times higher to about 400 times higher; fromabout 5 times higher to about 300 times higher; from about 5 timeshigher to about 200 times higher; from about 5 times higher to about 100times higher; from about 5 times higher to about 50 times higher; fromabout 5 times higher to about 25 times higher; from about 5 times higherto about 15 times higher; e.g., about 1,000 times higher, about 900times higher, about 800 times higher, about 700 times higher, about 600times higher, about 500 times higher, about 400 times higher, about 300times higher, about 200 times higher, about 100 times higher, about 50times higher, about 25 time higher, about 20 times higher, about 15times higher, about 10 times higher, about 5 times higher) than theconcentration of the chemical entity in the plasma compartment. Incertain of these embodiments, the chemical entity in the plasmacompartment is subject to first pass metabolism.

In some embodiments, the niclosamide compound described herein or apharmaceutical composition thereof are suitable for local administrationto one or more specific locations within the respiratory tract. Forexample, at least some of the niclosamide compound is present in theupper respiratory tract (e.g., nose and nasal passages, paranasalsinuses, the pharynx, and the portion of the larynx above the vocalfolds (cords) (e.g., nose and nasal passages); or at least some of theniclosamide compound is present in the lower respiratory tract (e.g.,portion of the larynx below the vocal folds, trachea, bronchi, and lungs(e.g., lungs)). Methods of said local administration can include,without limitation, respiratory administration such as inhalation orintranasal administration.

In some embodiments, the niclosamide compound described herein or apharmaceutical composition thereof are suitable for local administrationto the GI tract, e.g., colon. In certain embodiments, uponadministration, the local concentration of the niclosamide compound inthe GI tract is higher (e.g., from about 2 times higher to about 1,000times higher; from about 2 times higher to about 900 times higher; fromabout 2 times higher to about 800 times higher; from about 2 timeshigher to about 700 times higher; from about 2 times higher to about 500times higher; from about 2 times higher to about 400 times higher; fromabout 2 times higher to about 300 times higher; from about 2 timeshigher to about 200 times higher; from about 2 times higher to about 100times higher; from about 2 times higher to about 50 times higher, fromabout 5 times higher to about 1,000 times higher; from about 5 timeshigher to about 900 times higher; from about 5 times higher to about 800times higher; from about 2 times higher to about 700 times higher; fromabout 5 times higher to about 500 times higher; from about 5 timeshigher to about 400 times higher; from about 5 times higher to about 300times higher; from about 5 times higher to about 200 times higher; fromabout 5 times higher to about 100 times higher; from about 5 timeshigher to about 50 times higher; from about 5 times higher to about 25times higher; from about 5 times higher to about 15 times higher; e.g.,about 1,000 times higher, about 900 times higher, about 800 timeshigher, about 700 times higher, about 600 times higher, about 500 timeshigher, about 400 times higher, about 300 times higher, about 200 timeshigher, about 100 times higher, about 50 times higher, about 25 timehigher, about 20 times higher, about 15 times higher, about 10 timeshigher, about 5 times higher) than the concentration of the chemicalentity in the plasma compartment. In certain of these embodiments, thechemical entity in the plasma compartment is subject to first passmetabolism.

In some embodiments, the niclosamide compound described herein or apharmaceutical composition thereof are suitable for local administrationto one or more specific locations within the digestive or GI tract,e.g., colon. For example, at least some of the niclosamide compound ispresent in the upper GI tract (e.g., stomach); or at least some of theniclosamide compound is present in the lower GI tract (e.g., the largeintestine, e.g., the colon, e.g., the ascending colon and/or transversecolon and/or distal colon; or the small bowel). As a further example, atleast some of the niclosamide compound is present in the ascending colonand/or the transverse colon and/or the distal colon and/or the smallbowel and/or the stomach. Methods of said local administration caninclude, without limitation, oral administration and/or rectaladministration.

In one aspect, provided herein is a composition comprising a niclosamidecompound or co-crystal as described anywhere herein and one or morepharmaceutically acceptable excipients, wherein the composition issuitable for oral administration.

In one aspect, provided herein is a composition comprising a niclosamidecompound or co-crystal as described anywhere herein and one or morepharmaceutically acceptable excipients, wherein the composition issuitable for local, topical administration. In certain embodiments, thechemical entities described herein or a pharmaceutical compositionthereof are suitable for rectal administration. Rectal compositionsinclude, without limitation, enemas, rectal gels, rectal foams, rectalaerosols, suppositories, jelly suppositories, and enemas (e.g.,retention enemas).

Pharmacologically acceptable excipients usable in the rectal compositionas a gel, cream, enema, or rectal suppository, include, withoutlimitation, any one or more of cocoa butter glycerides, syntheticpolymers such as polyvinylpyrrolidone, PEG (like PEG ointments),glycerine, glycerinated gelatin, hydrogenated vegetable oils,poloxamers, mixtures of polyethylene glycols of various molecularweights and fatty acid esters of polyethylene glycol Vaseline, anhydrouslanolin, shark liver oil, sodium saccharinate, menthol, sweet almondoil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil,aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodiumpropyl p-oxybenzoate, diethylamine, carbomers, carbopol,methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate,isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum,carboxy-metabisulfite, sodium edetate, sodium benzoate, potassiummetabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM),lactic acid, glycine, vitamins, such as vitamin A and E and potassiumacetate.

In certain embodiments, suppositories can be prepared by mixing thechemical entities described herein with suitable non-irritatingexcipients or carriers such as cocoa butter, polyethylene glycol or asuppository wax which are solid at ambient temperature but liquid atbody temperature and therefore melt in the rectum and release the activecompound. In other embodiments, compositions for rectal administrationare in the form of an enema.

In some embodiments, administration of a single dose of the compositionto a subject produces a local concentration of the niclosamide compoundin the GI tract (e.g., colon) of the subject that is higher than theconcentration of the compound in the plasma compartment of the subject.

In some embodiments, administration of a single dose of the compositionto a subject produces a local concentration of the niclosamide compoundin the GI tract (e.g., colon) of the subject that is at least about 200times higher than the concentration of the compound in the plasmacompartment of the subject.

In some embodiments, administration of a single dose of the compositionto a subject produces a local concentration of the niclosamide compoundin the GI tract (e.g., colon) of the subject that is at least about 300times higher than the concentration of the compound in the plasmacompartment of the subject.

In some embodiments, administration of a single dose of the compositionto a subject produces a local concentration of the niclosamide compoundin the GI tract (e.g., colon) of the subject that is at least about 500times higher than the concentration of the compound in the plasmacompartment of the subject.

In some embodiments, administration of a single dose of the compositionto a subject produces a local concentration of the niclosamide compoundin the GI tract (e.g., colon) of the subject that is at least about 700times higher than the concentration of the compound in the plasmacompartment of the subject.

In some embodiments, the local concentration of the niclosamide compoundin the GI tract (e.g., colon) of the subject is higher than a localconcentration produced by oral administration of a single dose of asecond composition comprising a second niclosamide compound, wherein thesecond niclosamide compound has a higher particle size than the firstniclosamide compound.

In some embodiments, the local concentration of the niclosamide compoundin the GI tract (e.g., colon) of the subject is at least about 2 timeshigher than a local concentration produced by oral administration of asingle dose of a second composition comprising a second niclosamidecompound, wherein the second niclosamide compound has a higher particlesize than the first niclosamide compound.

In some embodiments, the local concentration of the niclosamide compoundin the GI tract (e.g., colon) of the subject is at least about 5 timeshigher than a local concentration produced by oral administration of asingle dose of a second composition comprising a second niclosamidecompound, wherein the second niclosamide compound has a higher particlesize than the first niclosamide compound.

In some embodiments, the local concentration of the niclosamide compoundin the GI tract (e.g., colon) of the subject is at least about 10 timeshigher than a local concentration produced by oral administration of asingle dose of a second composition comprising a second niclosamidecompound, wherein the second niclosamide compound has a higher particlesize than the first niclosamide compound.

In some embodiments, the local concentration of the niclosamide compoundin the GI tract (e.g., colon) of the subject is at least about 25 timeshigher than a local concentration produced by oral administration of asingle dose of a second composition comprising a second niclosamidecompound, wherein the second niclosamide compound has a higher particlesize than the first niclosamide compound.

In some embodiments, the local concentration of the niclosamide compoundin the GI tract (e.g., colon) of the subject is at least about 50 timeshigher than a local concentration produced by oral administration of asingle dose of a second composition comprising a second niclosamidecompound, wherein the second niclosamide compound has a higher particlesize than the first niclosamide compound.

In some embodiments, the local concentration of the niclosamide compoundin the GI tract (e.g., colon) of the subject is at least about 100 timeshigher than a local concentration produced by oral administration of asingle dose of a second composition comprising a second niclosamidecompound, wherein the second niclosamide compound has a higher particlesize than the first niclosamide compound.

In some embodiments, the second niclosamide compound has a particle sizedistribution D(0.9) of from about 25.0 μm to about 65.0 μm.

In some embodiments, the second niclosamide compound has a particle sizedistribution D(0.1) of from about 4.0 μm to about 10.0 μm.

In another aspect, provided herein is a dosage form (e.g., a unit dosageform) comprising a composition as described anywhere herein, wherein thedosage form is suitable for oral administration.

In another aspect, provided herein is a dosage form (e.g., a unit dosageform) comprising a composition as described anywhere herein, wherein thedosage form is suitable for rectal administration.

In some embodiments, the dosage form further comprises one or morecomponents that chemically and/or structurally predispose the dosageform for delivery of the compound to the ascending colon.

In some embodiments, the dosage form further comprises one or morecomponents that chemically and/or structurally predispose the dosageform for delivery of the compound to the transverse colon.

In some embodiments, the dosage form further comprises one or morecomponents that chemically and/or structurally predispose the dosageform for delivery of the compound to the distal colon.

In some embodiments, the dosage form further comprises one or morecomponents that chemically and/or structurally predispose the dosageform for delivery of the compound to the small bowel.

In one aspect, provided herein is a composition comprising a niclosamidecompound or co-crystal as described anywhere herein and one or morepharmaceutically acceptable excipients, wherein the composition issuitable for respiratory administration (e.g., inhalation).

In some embodiments, administration of a single dose of the compositionto a subject produces a local concentration of the niclosamide compoundin the lower respiratory tract (e.g., lungs) of the subject that ishigher than the concentration of the compound in the upper respiratorytract of the subject.

Inhalation and Intranasal Therapy

In some embodiments, niclosamide or a pharmaceutically acceptable saltthereof can be formulated into any suitable dosage form. Non-limitingexamples of such dosage forms include aerosols, dispersions (e.g.,aqueous oral dispersions, self-emulsifying dispersions, liposomaldispersions, dispersions with colloidal silica or nanospheres such ashydroxypropylmethylcellulose phthalate (HPMCP) nanospheres), pegylatedliposomes, liquids, elixirs, suspensions (e.g., nanosuspensions),aerosols, controlled release formulations, lyophilized formulations,powders, delayed release formulations, extended release formulations,multiparticulate formulations, and mixed immediate release formulations.In some embodiments, niclosamide or a pharmaceutically acceptable saltthereof, can be formulated for administration intranasally and/or byinhalation, e.g., using an inhalation device.

An “inhalation device,” as used herein, refers to any device that iscapable of administering a drug formulation to the respiratory airwaysof a subject. Inhalation devices include conventional inhalation devicessuch as nebulizers, metered dose inhalers (MDIs), dry powder inhalers(DPIs), heat vaporizers, soft mist inhalers, thermal aerosol inhalers,or electrohydrodynamic-based solution misting inhalers. Inhalationdevices also include nebulizers. “Nebulizer,” as used herein, refers toa device that turns medications, compositions, formulations,suspensions, and mixtures, etc. into a fine aerosol mist for delivery tothe lungs. Non-limiting examples of nebulizers include jet nebulizers,mesh nebulizers, and ultrasonic wave nebulizers. Nebulizers, metereddose inhalers, and soft mist inhalers deliver pharmaceuticals by formingan aerosol which includes droplet sizes that can easily be inhaled. Theaerosol can be used by a subject within the bounds of an inhalationtherapy, whereby the niclosamide or a pharmaceutically-acceptable saltthereof reaches the subject's respiratory tract upon inhalation. In someembodiments, the methods disclosed herein comprise administering to asubject a nominal dose of niclosamide or a pharmaceutically-acceptablesalt thereof by an inhalation device, such as a nebulizer.

In some embodiments of the methods disclosed herein, administration of acomposition comprising niclosamide or a pharmaceutically acceptable saltthereof, to a subject with an inhalation device, e.g., a nebulizer, ametered dose inhaler, a dry powder inhaler (DPI), a jet nebulizer, anultrasonic wave nebulizer, a heat vaporizer, a soft mist inhaler, athermal aerosol inhaler, or an electrohydrodynamic-based solutionmisting inhaler, is effective for the treatment or prophylaxis ofCOVID-19 in a subject.

Inhalation devices may be mechanical or electrical, and include, forexample, jet nebulizers and ultrasonic nebulizers. Jet nebulizersgenerally utilize compressors to generate compressed air, which breaksthe liquid medication into small breathable droplets, which form anaerosolized (atomized) mist. In some embodiments, when the subjectbreathes in, a valve at the top opens, which then allows air into theapparatus, thereby increasing the rate of mist generation; when thesubject breathes out, the top valve closes, thereby slowing down mistgeneration while simultaneously permitting the subject to breathe outthrough the opening of a mouthpiece flap. Some nebulizers may providethe aerosol in a continuous mode (e.g., the eFlow from PARI PharmaStarnberg), by a breath enhanced mode (e.g., the PART LC Plus or Sprintfrom PARI Starnberg), by breath actuated mode dependent on the breathingpattern of the subject (e.g., the AeroEclipse from Trudell, Canada orthe I-Neb from Philips Respironics), or according to given inhalationprofile (e.g., the Akita from Activaero, Gmuenden, Germany).

Some conventional inhalation devices are disclosed in U.S. Pat. Nos.9,566,399, 6,513,727, 6,513,519, 6,176,237, 6,085,741, 6,000,394,5,957,389, 5,740,966, 5,549,102, 5,461,695, 5,458,136, 5,312,046,5,309,900, 5,280,784, and 4,496,086, and International Publication Nos.WO 2018/191776 and WO 2018/213834, each of which is hereby incorporatedby reference in its entirety. Commercial conventional inhalation devicesare available from: PARI (Germany) under the trade names PARI LC Plus®,LC Star®, and PARI-Jet®; A & H Products, Inc. (Tulsa, Okla.) under thetrade name AquaTower®; Hudson RCI (Temecula, Calif.) under the tradename AVA-NEB®; Intersurgical, Inc. (Liverpool, N.Y.) under the tradename Cirrus®; Salter Labs (Arvin, Calif.) under the trade name Salter8900®; Respironics (Murrysville, Pa.) under the trade name Sidestream®;Bunnell (Salt Lake City, Utah) under the trade name Whisper Jet®;Smiths-Medical (Hyth Kent, UK) under the trade name Downdraft®, andDeVilbiss (Somerset, Pa.) under the trade name DeVilbiss®; or Trudell,Canada under the trade name AeroEclipse®.

In some embodiments of the methods disclosed herein, compositionscomprising niclosamide or a pharmaceutically acceptable salt thereof areadministered with a dry powder inhaler. Compositions administered withdry powder inhalers can include nanoparticles, spray dried materials,engineered porous particles with low mass median diameter but a highgeometric diameter, liposomes, stealth (or PEGylated) liposomes, orcombinations thereof. In some embodiments, compositions administered bydry powder inhalers administered in the methods disclosed hereincomprise nanoparticle clusters that aggregate into micrometer sizedparticles at neutral or basic pH but dissociate into nanoparticles atthe pH encountered in the lung. In some embodiments the nanoparticleclusters comprise fumaryl diketopiperazine. In some embodiments,compositions administered with dry powder inhalers comprise lactose.

In some embodiments, a dry powder inhaler used to administer aninhalation formulation in the methods disclosed herein comprises apre-metered dose. For example a pre-metered dose inhaler can comprise acapsule pre-filled with a powder (e.g., a Plastiape Monodose inhaler).In some embodiments, a dry powder inhaler used to administer aninhalation formulation in the methods disclosed herein has adevice-metered system such as Twisthaler, sold by Schering Plough, whichcomprises a reservoir to store a powder and a twisting top to dispenseeach dose. Inhalation formulations for administration with a dry powderinhaler may be prepared by blending niclosamide or a pharmaceuticallyacceptable salt thereof, with lactose, or spray drying niclosamide or apharmaceutically acceptable salt thereof, or by pelletizing niclosamideor a pharmaceutically acceptable salt thereof, to form free-flowingspherical agglomerates.

In some embodiments of the methods disclosed herein, compositionscomprising niclosamide or a pharmaceutically acceptable salt thereof areadministered with a metered dose inhaler. In some embodiments, acomposition administered with a metered dose inhaler in the methodsdisclosed herein comprises one or more of nanoparticles, spray driedmaterials, engineered porous particles with low mass median diameter buta high geometric diameter, liposomes, and stealth (or PEGylated)liposomes.

In some embodiments of the methods disclosed herein, compositionscomprising niclosamide or a pharmaceutically acceptable salt thereof areadministered with a thermal aerosol inhaler.

In some embodiments of the methods disclosed herein, compositionscomprising niclosamide or a pharmaceutically acceptable salt thereof areadministered with an electrohydrodynamic-based solution misting inhaler.In some embodiments, the aerosol in the electrohydrodynamic-basedsolution-misting inhaler is generated by subjecting a solution ofniclosamide or a pharmaceutically acceptable salt thereof, or a liposomeor pegylated liposome comprising niclosamide or a pharmaceuticallyacceptable salt thereof, to electrohydrodynamic forces throughelectrostatic energy.

Nebulizers are inhalation devices that comprise a micro-perforatedmembrane through which a liquid solution is converted through electricalor mechanical means into aerosol droplets suitable for inhalation.Nebulizers can deliver a large fraction of a loaded dose to a subject.In some embodiments, the nebulizer also utilizes one or more actively orpassively vibrating microperforated membranes. In some embodiments, thenebulizer contains one or more oscillating membranes. In someembodiments, the nebulizer contains a vibrating mesh or plate withmultiple apertures and optionally a vibration generator with an aerosolmixing chamber. In some such embodiments, the mixing chamber functionsto collect (or stage) the aerosol from the aerosol generator. In someembodiments, an inhalation valve is also used to allow an inflow ofambient air into the mixing chamber during an inhalation phase and isclosed to prevent escape of the aerosol from the mixing chamber duringan exhalation phase. In some such embodiments, the exhalation valve isarranged at a mouthpiece which is removably mounted at the mixingchamber and through which the subject inhales the aerosol from themixing chamber. Still yet, in some embodiments, the nebulizer contains apulsating membrane. In some embodiments, the nebulizer is continuouslyoperating.

In some embodiments, the nebulizer contains a vibrating micro-perforatedmembrane of tapered nozzles that generates a plume of droplets withoutthe need for compressed gas. In these embodiments, a solution in themicro-perforated membrane nebulizer is in contact with a membrane, theopposite side of which is open to the air. The membrane is perforated bya large number of nozzle orifices of an atomizing head. An aerosol iscreated when alternating acoustic pressure in the solution is built upin the vicinity of the membrane causing the fluid on the liquid side ofthe membrane to be emitted through the nozzles as uniformly sizeddroplets.

Some embodiments of nebulizers use passive nozzle membranes and aseparate piezoelectric transducer that stimulates the membrane. Incontrast, some nebulizers employ an active nozzle membrane, which usethe acoustic pressure in the nebulizer to generate very fine droplets ofsolution via the high frequency vibration of the nozzle membrane.

Some nebulizers can contain a resonant system. For example, in suchnebulizers, the membrane is driven by a frequency for which theamplitude of the vibrational movement at the center of the membrane isparticularly large, resulting in a focused acoustic pressure in thevicinity of the nozzle; the resonant frequency may be about 100 kHz. Aflexible mounting is used to keep unwanted loss of vibrational energy tothe mechanical surroundings of the atomizing head to a minimum. In someembodiments, the vibrating membrane of the nebulizer may be madestainless steel, or of a nickel-palladium alloy by electroforming.

In some embodiments, a nebulizer may be adapted or adaptable to operatein conjunction with a unit dosage form, such as an ampule or vial, whichcontains a single dose of a composition comprising niclosamide, or apharmaceutically-acceptable salt thereof, for the treatment of COVID-19.The unit dosage form comprises a container that contains an inhalationformulation comprising the niclosamide, or a pharmaceutically-acceptablesalt thereof. The container is adapted to cooperate with the nebulizerdevice in such a way as to permit administration of the nominal dose ofthe inhalation formulation to a subject. In some embodiments, thenebulizer and the unit dosage form are configured so that they areuseable together, but not with other devices or dosage forms. In someparticular embodiments, the unit dosage form is configured such that itfits into a keyhole-like structure in the nebulizer, but will notoperate with other nebulizer devices. In such embodiments, the nebulizeris configured such that it will accept and properly operate with theunit dosage form containing the niclosamide, or apharmaceutically-acceptable salt thereof, but not with other dosageforms.

Commercial high efficiency nebulizers are available from: PARI (Germany)under the trade name eFlow®; Aerogen, Ltd. (Ireland) under the tradenames AeroNeb® Go and AeroNeb® Pro, AeroNeb® Solo, and other nebulizersutilizing the OnQ® nebulizer technology; Respironics (Murrysville,Calif.) under the trade names I-Neb®, Omron (Bannockburn, Ill.) underthe trade name Micro-Air®; Activaero (Germany) under the trade nameAkita®, and AerovectRx (Atlanta, Ga.) under the trade name AerovectRx®.

In some embodiments, a composition comprising niclosamide, or apharmaceutically acceptable salt thereof, is formulated as an inhalablenanosuspension (see, e.g., Costabile et al. Mol Pharm. 2015 Aug. 3;12(8):2604-17.) In some embodiments, an inhalable nanosuspension ofniclosamide, or a pharmaceutically acceptable salt thereof, isadministered to a subject using a nebulizer.

In some embodiments, devices for intranasal administration ofniclosamide, or a pharmaceutically acceptable salt thereof, include oneor more features present in any inhalation device described herein. Insome embodiments, devices for intranasal administration of niclosamide,or a pharmaceutically acceptable salt thereof, are spray devices.Suitable commercially available nasal spray devices include Accuspray™(Becton Dickinson). In some embodiments, spray devices for intranasaluse are devices for which the performance of the device is not dependentupon the pressure applied by the user. These devices are known aspressure threshold devices. Pressure threshold devised release liquidfrom the nozzle only when a threshold pressure is applied. These devicesmake it easier to achieve a spray with a regular droplet size. Pressurethreshold devices suitable for use with the present invention are knownin the art and are described for example in WO 91/13281, EP 3111863, andEP 516636. Pressure threshold devices are commercially available fromPfeiffer GmbH and are also described in Bommer, R. PharmaceuticalTechnology Europe, September 1999.

In some embodiments, the intranasal devices can administer niclosamide;or a pharmaceutically acceptable salt thereof, by means of bi-dosedelivery. Bi-dose devices contain two sub-doses of a single dose, onesub-dose for administration to each nostril. Generally, the twosub-doses are present in a single chamber and the construction of thedevice allows for efficient delivery of a single sub-dose at a time.Alternatively, a monodose device may be used for administering thevaccines according to the invention.

In some embodiments, niclosamide, or a pharmaceutically acceptable saltthereof, is formulated as an ointment or gel for intranasal delivery.

In some embodiments, the compositions disclosed herein can include oneor pharmaceutical excipients that provide suitable properties forintranasal administration and/or administration by inhalation ofniclosamide, or a pharmaceutically acceptable salt thereof. See, e.g.,Labiris and Dolovich, Br J Clin Pharmacol. 2003 December; 56(6):600-612. Non-limiting examples of such pharmaceutical excipients caninclude surfactants, suspending agents, viscosity enhancing agents,wetting agents, and propellants.

“Suspending agents” include compounds such as polyvinylpyrrolidone,e.g., polyvinylpyrrolidone. K12, polyvinylpyrrolidone K17,polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone/vinyl acetate copolymer (S630), polyethylene glycol, e.g.,the polyethylene glycol can have a molecular weight of about 300 toabout 6000, or about 3350 to about 4000, or about 7000 to about 5400,sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,gum tragacanth and gum acacia, guar gum, xanthans, including xanthangum, sugars, cellulosics, such as, e.g., sodium carboxylmethylcellulose,methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, poiyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

“Surfactants” include compounds such as sodium lauryl sulfate, sodiumdocusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitanmonooleate, polyoxyethylene sorbitan monooleate, polysorbates,polaxomers, bile salts, glyceryl monostearate, copolymers of ethyleneoxide and propylene oxide, e.g., Pluronic® (BASF), and the like.Additional examples of surfactants include polyoxyethylene fatty acidglycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenatedcastor oil; and polyoxyethylene alkylethers and alkylphenyl ethers,e.g., octoxynol 10, octoxynol 40.

“Viscosity enhancing agents” include, e.g., methyl cellulose, xanthangum, carboxymethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetatestearate, hydroxypropylmethyl cellulose phthalate; carbomer, polyvinylalcohol, alginates, acacia, chitosans, and combinations thereof.

“Wetting agents” include compounds such as oleic acid, glycerylmonostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamineoleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate,sodium doccusate, triacetin, Tween 80, vitamin E TPGS, ammonium saltsand the like.

Non-limiting examples of propellants include chlorofluorocarbons (CFC)and hydrofluoroalkanes (HFAs).

Compositions and formulations of the disclosure may have a surfacetension effective for deposition, penetration or retention of thecomposition primarily in the peripheral lung regions, including thebronchioles and alveoli.

Oral Delivery

In other embodiments, the chemical entities described herein or apharmaceutical composition thereof are suitable for local delivery tothe digestive or GI tract by way of oral administration (e.g., solid orliquid dosage forms).

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the chemicalentity is mixed with one or more pharmaceutically acceptable excipients,such as sodium citrate or dicalcium phosphate and/or: a) fillers orextenders such as starches, lactose, sucrose, glucose, mannitol, andsilicic acid, b) binders such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c)humectants such as glycerol, d) disintegrating agents such as agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certainsilicates, and sodium carbonate, e) solution retarding agents such asparaffin, f) absorption accelerators such as quaternary ammoniumcompounds, g) wetting agents such as, for example, cetyl alcohol andglycerol monostearate, h) absorbents such as kaolin and bentonite clay,and i) lubricants such as talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.In the case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugar as well as high molecularweight polyethylene glycols and the like.

In one embodiment, the compositions will take the form of a unit dosageform such as a pill or tablet and thus the composition may contain,along with a chemical entity provided herein, a diluent such as lactose,sucrose, dicalcium phosphate, or the like; a lubricant such as magnesiumstearate or the like; and a binder such as starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or thelike. In another solid dosage form, a powder, marume, solution orsuspension (e.g., in propylene carbonate, vegetable oils, PEG's,poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin orcellulose base capsule). Unit dosage forms in which one or more chemicalentities provided herein or additional active agents are physicallyseparated are also contemplated; e.g., capsules with granules (ortablets in a capsule) of each drug; two-layer tablets; two-compartmentgel caps, etc. Enteric coated or delayed release oral dosage forms arealso contemplated.

Other physiologically acceptable compounds include wetting agents,emulsifying agents, dispersing agents or preservatives that areparticularly useful for preventing the growth or action ofmicroorganisms. Various preservatives are well known and include, forexample, phenol and ascorbic acid.

In certain embodiments the excipients are sterile and generally free ofundesirable matter. These compositions can be sterilized byconventional, well-known sterilization techniques. For various oraldosage form excipients such as tablets and capsules sterility is notrequired. The USP/NF standard is usually sufficient.

In certain embodiments, solid oral dosage forms can further include oneor more components that chemically and/or structurally predispose thecomposition for delivery of the chemical entity to the stomach or thelower GI; e.g., the ascending colon and/or transverse colon and/ordistal colon and/or small bowel. Exemplary formulation techniques aredescribed in, e.g., Filipski, K. J., et al., Current Topics in MedicinalChemistry, 2013, 13, 776-802, which is incorporated herein by referencein its entirety.

Examples include upper-GI targeting techniques, e.g., Accordion Pill(Intec Pharma), floating capsules, and materials capable of adhering tomucosal walls.

Other examples include lower-GI targeting techniques. For targetingvarious regions in the intestinal tract, several enteric/pH-responsivecoatings and excipients are available. These materials are typicallypolymers that are designed to dissolve or erode at specific pH ranges,selected based upon the GI region of desired drug release. Thesematerials also function to protect acid labile drugs from gastric fluidor limit exposure in cases where the active ingredient may be irritatingto the upper GI (e.g., hydroxypropyl methylcellulose phthalate series,Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate,hydroxypropyl methylcellulose acetate succinate, Eudragit series(methacrylic acid-methyl methacrylate copolymers), and Marcoat). Othertechniques include dosage forms that respond to local flora in the GItract, Pressure-controlled colon delivery capsule, and Pulsincap.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the chemical entities described herein, theliquid dosage forms may contain inert diluents commonly used in the artsuch as, for example, water or other solvents, solubilizing agents andemulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents. In certain embodiments, the liquid dosage form is a mouthwash.In certain embodiments, such liquid oral dosage forms are useful forlocal and topical administration to the digestive or GI tract, e.g.,digestive tract, e.g., oral cavity.

Orally administered niclosamide can be delivered to the digestive tract(e.g., the colon) using one or more delivery systems. Non-limitingexamples of delivery systems include: prodrugs (e.g., azo-conjugates,pectin prodrugs, or prodrugs formed by conjugation (e.g., throughazo-bond) to one or more carrier molecules such as cyclodextrin,glucuronide, dextran, amino acids (e.g., sodium alginate), and HMPC);biodegradable delivery systems (e.g., colon-specific biodegradabledelivery systems) (e.g., biodegradable delivery systems using guar gumand derivatives thereof (e.g., AcGGM), azo-aromatic polymers);matrix-based systems (e.g., by embedding niclosamide in polymer matricessuch as starch derived polymer matrices (e.g., pH-sensitive and/orbiodegradable matrices such as Assam Bora rice starch matrices));time-released systems (e.g., using pH sensitive polymers); bioadhesivesystems (e.g., using polymers such as polycarbophils, polyurethanes,polyethylene oxide, Assam Bora rice starch); multiparticulate systems(e.g., using microspheres (e.g., biodegradable microspheres) such aschitosan microspheres (e.g., coated with Eudragit), guar gum basemicrospheres, polysaccharide pectins, pectin-4-aminothiophenol (Pec-ATP)conjugates, calcium alginate-carboxymethyl cellulose (CA-CMC),nanoparticles (e.g., with MMT-K10 clay), each of which can be optionallycoated with a pH sensitive polymer (e.g., Eudragit));polysaccharide-based delivery systems (e.g., with xanthan gum, guar gum,pectin (e.g., mixture with an insoluble polymer such as ethylcellulose), chitosan, HPMC derivatives, chondroitin sulfate,galactomannan, amylose, or combinations of polysaccharides such ascombinations of cellulose derivatives (e.g., combinations of non-entericcellulose esters such as cellulose acetate and enteric cellulose esterssuch as CAP and HPMCP; e.g., pectin-HPMC, chitosan-HPMC,chitosan-pectin, guar gum-chitosan, and dextran-chitosan)); coatings(e.g., with pH sensitive polymers such as enteric-soluble polymers suchas methacrylic-acid based polymers (e.g., Eudragit, Eudragit L, orEudragit S) or Landolphia owariensis latex (LOL), with acid-solublepolymers such as Eudragit E, with pulsatile coatings, with rupturablefilm coatings, with permeable or semi-permeable film coatings, andoptionally using compression-coating systems wherein the core tabletcomprising niclosamide and one or more polymer coatings is furthercoated with a coating excipient (e.g., almond-gum matrix);pressure-controlled delivery systems; osmotic controlled deliverysystems (e.g., OROS-CT); and pulsincap systems. Additional examples aredescribed in Amido, AAPS PharmSciTech, Vol. 16, No. 4, August 2015,which is incorporated herein by reference in its entirety.

Non-limiting examples of oral dosage forms suitable for the selectivedelivery to the digestive tract (e.g., to the colon) include: delayedrelease tablets; timed release capsules; immediate release tablets;immediate release capsules (e.g., soft gelatin immediate releasecapsules); multi-matrix tablets; extended release tablets;gastro-resistant prolonged-release tablets; oral colon-targeted pellets;oral solutions; and oral powders. Additional examples are described inAmido, AAPS PharmSciTech, Vol. 16, No. 4, August 2015, which isincorporated herein by reference in its entirety.

Further non-limiting examples of dosage forms suitable for selectivedelivery to the digestive tract (e.g., to the colon) include thosedescribed in U.S. Pat. Nos. 9,192,583; 6,224,910; 5,914,132; 9,237,760;9,023,368; 6,228,396; 10,588,864; Int. J. Appl. Res. Nat. Prod., 2012,5, 1-16; Carbohydrate Polymers, 2013, 92, 367-373; and J. ControlledRelease, 1996, 38, 75-94, each of which is incorporated herein byreference in its entirety.

Enema Formulations

In some embodiments, enema formulations containing the chemical entitiesdescribed herein are provided in “ready-to-use” form.

In some embodiments, enema formulations containing the chemical entitiesdescribed herein are provided in one or more kits or packs. In certainembodiments, the kit or pack includes two or more separatelycontained/packaged components, e.g. two components, which when mixedtogether, provide the desired formulation (e.g., as a suspension). Incertain of these embodiments, the two component system includes a firstcomponent and a second component, in which: (1) the first component(e.g., contained in a sachet) includes the chemical entity (as describedanywhere herein) and optionally one or more pharmaceutically acceptableexcipients (e.g., together formulated as a solid preparation, e.g.,together formulated as a wet granulated solid preparation); and (ii) thesecond component (e.g., contained in a vial or bottle) includes one ormore liquids and optionally one or more other pharmaceuticallyacceptable excipients together forming a liquid carrier. Prior to use(e.g., immediately prior to use), the contents of (1) and (ii) arecombined to form the desired enema formulation, e.g., as a suspension.In other embodiments, each of component (1) and (ii) is provided in itsown separate kit or pack.

In some embodiments, each of the one or more liquids is water, or aphysiologically acceptable solvent, or a mixture of water and one ormore physiologically acceptable solvents. Typical such solvents include,without limitation, glycerol, ethylene glycol, propylene glycol,polyethylene glycol and polypropylene glycol. In certain embodiments,each of the one or more liquids is water. In other embodiments, each ofthe one or more liquids is an oil, e.g. natural and/or synthetic oilsthat are commonly used in pharmaceutical preparations.

Further pharmaceutical excipients and carriers that may be used in thepharmaceutical products herein described are listed in various handbooks(e.g. D. E. Bugay and W. P. Findlay (Eds) Pharmaceutical excipients(Marcel Dekker, New York, 1999), E-M Hoepfner, A. Reng and P. C. Schmidt(Eds) Fiedler Encyclopedia of Excipients for Pharmaceuticals, Cosmeticsand Related Areas (Edition Cantor, Munich, 2002) and H. P. Fielder (Ed)Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete(Edition Cantor Aulendorf, 1989)).

In some embodiments, each of the one or more pharmaceutically acceptableexcipients can be independently selected from thickeners, viscosityenhancing agents, bulking agents, mucoadhesive agents, penetrationenhancers, buffers, preservatives, diluents, binders, lubricants,glidants, disintegrants, fillers, solubilizing agents, pH modifyingagents, preservatives, stabilizing agents, anti-oxidants, wetting oremulsifying agents, suspending agents, pigments, colorants, isotonicagents, chelating agents, emulsifiers, and diagnostic agents.

In certain embodiments, each of the one or more pharmaceuticallyacceptable excipients can be independently selected from thickeners,viscosity enhancing agents, mucoadhesive agents, buffers, preservatives,diluents, binders, lubricants, glidants, disintegrants, and fillers.

In certain embodiments, each of the one or more pharmaceuticallyacceptable excipients can be independently selected from thickeners,viscosity enhancing agents, bulking agents, mucoadhesive agents,buffers, preservatives, and fillers.

In certain embodiments, each of the one or more pharmaceuticallyacceptable excipients can be independently selected from diluents,binders, lubricants, glidants, and disintegrants.

Examples of thickeners, viscosity enhancing agents, and mucoadhesiveagents include without limitation: gums, e.g. xanthan gum, guar gum,locust bean gum, tragacanth gums, karaya gum, ghatti gum, cholla gum,psyllium seed gum and gum arabic; poly(carboxylic acid-containing) basedpolymers, such as poly (acrylic, maleic, itaconic, citraconic,hydroxyethyl methacrylic or methacrylic) acid which have stronghydrogen-bonding groups, or derivatives thereof such as salts andesters; cellulose derivatives, such as methyl cellulose, ethylcellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose,carboxymethyl cellulose, hydroxypropylmethyl cellulose or celluloseesters or ethers or derivatives or salts thereof; clays such asmanomorillonite clays, e.g. Veegun, attapulgite clay; polysaccharidessuch as dextran, pectin, amylopectin, agar, mannan or polygalactonicacid or starches such as hydroxypropyl starch or carboxymethyl starch;polypeptides such as casein, gluten, gelatin, fibrin glue; chitosan,e.g. lactate or glutamate or carboxymethyl chitin; glycosaminoglycanssuch as hyaluronic acid; metals or water soluble salts of alginic acidsuch as sodium alginate or magnesium alginate; schleroglucan; adhesivescontaining bismuth oxide or aluminium oxide; atherocollagen; polyvinylpolymers such as carboxyvinyl polymers; polyvinylpyrrolidone (povidone);polyvinyl alcohol; polyvinyl acetates, polyvinylmethyl ethers, polyvinylchlorides, polyvinylidenes, and/or the like; polycarboxylated vinylpolymers such as polyacrylic acid as mentioned above; polysiloxanes;polyethers; polyethylene oxides and glycols; polyalkoxys andpolyacrylamides and derivatives and salts thereof. Preferred examplescan include cellulose derivatives, such as methyl cellulose, ethylcellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose,carboxymethyl cellulose, hydroxypropylmethyl cellulose or celluloseesters or ethers or derivatives or salts thereof (e.g., methylcellulose); and polyvinyl polymers such as polyvinylpyrrolidone(povidone).

Examples of preservatives include without limitation: benzalkoniumchloride, benzoxonium chloride, benzethonium chloride, cetrimide,sepazonium chloride, cetylpyridinium chloride, domiphen bromide(Bradosol®), thiomersal, phenylmercuric nitrate, phenylmercuric acetate,phenylmercuric borate, methylparaben, propylparaben, chlorobutanol,benzyl alcohol, phenyl ethyl alcohol, chlorohexidine, polyhexamethylenebiguanide, sodium perborate, imidazolidinyl urea, sorbic acid, Purite®),Polyquart®), and sodium perborate tetrahydrate and the like.

In certain embodiments, the preservative is a paraben, or apharmaceutically acceptable salt thereof. In some embodiments, theparaben is an alkyl substituted 4-hydroxybenzoate, or a pharmaceuticallyacceptable salt or ester thereof. In certain embodiments, the alkyl is aC1-C4 alkyl. In certain embodiments, the preservative is methyl4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable saltor ester thereof, propyl 4-hydroxybenzoate (propylparaben), or apharmaceutically acceptable salt or ester thereof, or a combinationthereof.

Examples of buffers include without limitation: phosphate buffer system(sodium dihydrogen phospahate dehydrate, disodium phosphatedodecahydrate, bibasic sodium phosphate, anhydrous monobasic sodiumphosphate), bicarbonate buffer system, and bisulfate buffer system.

Examples of disintegrants include, without limitation: carmellosecalcium, low substituted hydroxypropyl cellulose (L-HPC), carmellose,croscarmellose sodium, partially pregelatinized starch, dry starch,carboxymethyl starch sodium, crospovidone, polysorbate 80(polyoxyethylenesorbitan oleate), starch, sodium starch glycolate,hydroxypropyl cellulose pregelatinized starch, clays, cellulose,alginine, gums or cross linked polymers, such as cross-linked PVP(Polyplasdone XL from GAF Chemical Corp). In certain embodiments, thedisintegrant is crospovidone.

Examples of glidants and lubricants (aggregation inhibitors) includewithout limitation: talc, magnesium stearate, calcium stearate,colloidal silica, stearic acid, aqueous silicon dioxide, syntheticmagnesium silicate, fine granulated silicon oxide, starch, sodiumlaurylsulfate, boric acid, magnesium oxide, waxes, hydrogenated oil,polyethylene glycol, sodium benzoate, stearic acid glycerol behenate,polyethylene glycol, and mineral oil. In certain embodiments, theglidant/lubricant is magnesium stearate, talc, and/or colloidal silica;e.g., magnesium stearate and/or talc.

Examples of diluents, also referred to as “fillers” or “bulking agents”include without limitation: dicalcium phosphate dihydrate, calciumsulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol,sorbitol, cellulose, microcrystalline cellulose, kaolin, sodiumchloride, dry starch, hydrolyzed starches, pregelatinized starch,silicone dioxide, titanium oxide, magnesium aluminum silicate andpowdered sugar. In certain embodiments, the diluent is lactose (e.g.,lactose monohydrate).

Examples of binders include without limitation: starch, pregelatinizedstarch, gelatin, sugars (including sucrose, glucose, dxtrose, lactoseand sorbitol), polyethylene glycol, waxes, natural and synthetic gumssuch as acacia tragacanth, sodium alginate cellulose, includinghydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose,and veegum, and synthetic polymers such as acrylic acid and methacrylicacid copolymers, methacrylic acid copolymers, methyl methacrylatecopolymers, aminoalkyl methacrylate copolymers, polyacrylicacid/polymethacrylic acid and polyvinylpyrrolidone (povidone). Incertain embodiments, the binder is polyvinylpyrrolidone (povidone).

In some embodiments, enema formulations containing the chemical entitiesdescribed herein include water and one or more (e.g., all) of thefollowing excipients:

-   -   One or more (e.g., one, two, or three) thickeners, viscosity        enhancing agents, binders, and/or mucoadhesive agents (e.g.,        cellulose or cellulose esters or ethers or derivatives or salts        thereof (e.g., methyl cellulose); and polyvinyl polymers such as        polyvinylpyrrolidone (povidone);    -   One or more (e.g., one or two; e.g., two) preservatives, such as        a paraben, e.g., methyl 4-hydroxybenzoate (methylparaben), or a        pharmaceutically acceptable salt or ester thereof, propyl        4-hydroxybenzoate (propylparaben), or a pharmaceutically        acceptable salt or ester thereof, or a combination thereof;    -   One or more (e.g., one or two; e.g., two) buffers, such as        phosphate buffer system (e.g., sodium dihydrogen phospahate        dehydrate, disodium phosphate dodecahydrate);    -   One or more (e.g., one or two, e.g., two) glidants and/or        lubricants, such as magnesium stearate and/or talc;    -   One or more (e.g., one or two; e.g., one) disintegrants, such as        crospovidone; and    -   One or more (e.g., one or two; e.g., one) diluents, such as        lactose (e.g., lactose monohydrate).

In certain of these embodiments, the chemical entity is a niclosamidecompound, or a pharmaceutically acceptable salt and/or hydrate and/orcocrystal thereof.

In certain embodiments, enema formulations containing the chemicalentities described herein include water, methyl cellulose, povidone,methylparaben, propylparaben, sodium dihydrogen phospahate dehydrate,disodium phosphate dodecahydrate, crospovidone, lactose monohydrate,magnesium stearate, and talc. In certain of these embodiments, thechemical entity is a niclosamide compound, or a pharmaceuticallyacceptable salt and/or hydrate and/or cocrystal thereof.

In certain embodiments, enema formulations containing the chemicalentities described herein are provided in one or more kits or packs. Incertain embodiments, the kit or pack includes two separatelycontained/packaged components, which when mixed together, provide thedesired formulation (e.g., as a suspension). In certain of theseembodiments, the two component system includes a first component and asecond component, in which: (i) the first component (e.g., contained ina sachet) includes the chemical entity (as described anywhere herein)and one or more pharmaceutically acceptable excipients (e.g., togetherformulated as a solid preparation, e.g., together formulated as a wetgranulated solid preparation); and (ii) the second component (e.g.,contained in a vial or bottle) includes one or more liquids and one ormore one or more other pharmaceutically acceptable excipients togetherforming a liquid carrier. In other embodiments, each of component (i)and (ii) is provided in its own separate kit or pack.

In certain of these embodiments, component (i) includes the chemicalentity (e.g., a niclosamide compound, or a pharmaceutically acceptablesalt and/or hydrate and/or cocrystal thereof) and one or more (e.g.,all) of the following excipients:

-   -   (a) One or more (e.g., one) binders (e.g., a polyvinyl polymer,        such as polyvinylpyrrolidone (povidone);    -   (b) One or more (e.g., one or two, e.g., two) glidants and/or        lubricants, such as magnesium stearate and/or talc;    -   (c) One or more (e.g., one or two; e.g., one) disintegrants,        such as crospovidone; and    -   (d) One or more (e.g., one or two; e.g., one) diluents, such as        lactose (e.g., lactose monohydrate).

In certain embodiments, component (i) includes from about 40 weightpercent to about 80 weight percent (e.g., from about 50 weight percentto about 70 weight percent, from about 55 weight percent to about 70weight percent; from about 60 weight percent to about 65 weight percent;e.g., about 62.1 weight percent) of the chemical entity (e.g., aniclosamide compound, or a pharmaceutically acceptable salt and/orhydrate and/or cocrystal thereof).

In certain embodiments, component (i) includes from about 0.5 weightpercent to about 5 weight percent (e.g., from about 1.5 weight percentto about 4.5 weight percent, from about 2 weight percent to about 3.5weight percent; e.g., about 2.76 weight percent) of the binder (e.g.,povidone).

In certain embodiments, component (i) includes from about 0.5 weightpercent to about 5 weight percent (e.g., from about 0.5 weight percentto about 3 weight percent, from about 1 weight percent to about 3 weightpercent; about 2 weight percent e.g., about 1.9 weight percent) of thedisintegrant (e.g., crospovidone).

In certain embodiments, component (i) includes from about 10 weightpercent to about 50 weight percent (e.g., from about 20 weight percentto about 40 weight percent, from about 25 weight percent to about 35weight percent; e.g., about 31.03 weight percent) of the diluent (e.g.,lactose, e.g., lactose monohydrate).

In certain embodiments, component (i) includes from about 0.05 weightpercent to about 5 weight percent (e.g., from about 0.05 weight percentto about 3 weight percent) of the glidants and/or lubricants.

In certain embodiments (e.g., when component (i) includes one or morelubricants, such as magnesium stearate), component (i) includes fromabout 0.05 weight percent to about 1 weight percent (e.g., from about0.05 weight percent to about 1 weight percent; from about 0.1 weightpercent to about 1 weight percent; from about 0.1 weight percent toabout 0.5 weight percent; e.g., about 0.27 weight percent) of thelubricant (e.g., magnesium stearate).

In certain embodiments (when component (i) includes one or morelubricants, such as talc), component (i) includes from about 0.5 weightpercent to about 5 weight percent (e.g., from about 0.5 weight percentto about 3 weight percent, from about 1 weight percent to about 3 weightpercent; from about 1.5 weight percent to about 2.5 weight percent; fromabout 1.8 weight percent to about 2.2 weight percent; about 1.93 weightpercent) of the lubricant (e.g., talc).

In certain of these embodiments, each of (a), (b), (c), and (d) above ispresent.

In certain embodiments, component (i) includes the ingredients andamounts as shown in Table 7.

TABLE 7 Ingredient Weight Percent niclosamide compound 40 weight percentto about 80 weight percent (e.g., from about 50 weight percent to about70 weight percent, from about 55 weight percent to about 70 weightpercent; from about 60 weight percent to about 65 weight percent; e.g.,about 62.1 weight percent) Crospovidone 0.5 weight percent to about 5weight (Kollidon CL) percent (e.g., from about 0.5 weight percent toabout 3 weight percent, from about 1 weight percent to about 3 weightpercent; about 1.93 weight percent lactose monohydrate about 10 weightpercent to about 50 weight (Pharmatose 200M) percent (e.g., from about20 weight percent to about 40 weight percent, from about 25 weightpercent to about 35 weight percent; e.g., about 31.03 weight percentPovidone about 0.5 weight percent to about 5 weight (Kollidon K30)percent (e.g., from about 1.5 weight percent to about 4.5 weightpercent, from about 2 weight percent to about 3.5 weight percent; e.g.,about 2.76 weight percent talc 0.5 weight percent to about 5 weightpercent (e.g., from about 0.5 weight percent to about 3 weight percent,from about 1 weight percent to about 3 weight percent; from about 1.5weight percent to about 2.5 weight percent; from about 1.8 weightpercent to about 2.2 weight percent;e.g., about 1.93 weight percentMagnesium stearate about 0.05 weight percent to about 1 weight percent(e.g., from about 0.05 weight percent to about 1 weight percent; fromabout 0.1 weight percent to about 1 weight percent; from about 0.1weight percent to about 0.5 weight percent; e.g., about 0.27 weightpercent

In certain embodiments, component (1) includes the ingredients andamounts as shown in Table 8.

TABLE 8 Ingredient Weight Percent niclosamide compound About 62.1 weightpercent) Crospovidone (Kollidon CL) About 1.93 weight percent lactosemonohydrate About 31.03 weight percent (Pharmatose 200M) Povidone(Kollidon K30) About 2.76 weight percent talc About 1.93 weight percentMagnesium stearate About 0.27 weight percent

In certain embodiments, component (1) is formulated as a wet granulatedsolid preparation. In certain of these embodiments an internal phase ofingredients (the chemical entity, disintegrant, and diluent) arecombined and mixed in a high-shear granulator. A binder (e.g., povidone)is dissolved in water to form a granulating solution. This solution isadded to the Inner Phase mixture resulting in the development ofgranules. While not wishing to be bound by theory, granule developmentis believed to be facilitated by the interaction of the polymeric binderwith the materials of the internal phase. Once the granulation is formedand dried, an external phase (e.g., one or more lubricants—not anintrinsic component of the dried granulation), is added to the drygranulation. It is believed that lubrication of the granulation isimportant to the flowability of the granulation, in particular forpackaging. See, e.g., Example 8.

In certain of the foregoing embodiments, component (ii) includes waterand one or more (e.g., all) of the following excipients:

-   -   (a′) One or more (e.g., one, two; e.g., two) thickeners,        viscosity enhancing agents, binders, and/or mucoadhesive agents        (e.g., cellulose or cellulose esters or ethers or derivatives or        salts thereof (e.g., methyl cellulose); and polyvinyl polymers        such as polyvinylpyrrolidone (povidone);    -   (b′) One or more (e.g., one or two; e.g., two) preservatives,        such as a paraben, e.g., methyl 4-hydroxybenzoate        (methylparaben), or a pharmaceutically acceptable salt or ester        thereof, propyl 4-hydroxybenzoate (propylparaben), or a        pharmaceutically acceptable salt or ester thereof, or a        combination thereof; and    -   (c′) One or more (e.g., one or two; e.g., two) buffers, such as        phosphate buffer system (e.g., sodium dihydrogen phospahate        dihydrate, disodium phosphate dodecahydrate);

In certain of the foregoing embodiments, component (ii) includes waterand one or more (e.g., all) of the following excipients:

-   -   (a″) a first thickener, viscosity enhancing agent, binder,        and/or mucoadhesive agent (e.g., a cellulose or cellulose ester        or ether or derivative or salt thereof (e.g., methyl        cellulose));    -   (a′″) a second thickener, viscosity enhancing agent, binder,        and/or mucoadhesive agent (e.g., a polyvinyl polymer, such as        polyvinylpyrrolidone (povidone));    -   (b″) a first preservative, such as a paraben, e.g., propyl        4-hydroxybenzoate (propylparaben), or a pharmaceutically        acceptable salt or ester thereof;    -   (b″) a second preservative, such as a paraben, e.g., methyl        4-hydroxybenzoate (methylparaben), or a pharmaceutically        acceptable salt or ester thereof,    -   (c″) a first buffer, such as phosphate buffer system (e.g.,        disodium phosphate dodecahydrate);    -   (c′″) a second buffer, such as phosphate buffer system (e.g.,        sodium dihydrogen phospahate dehydrate),

In certain embodiments, component (ii) includes from about 0.05 weightpercent to about 5 weight percent (e.g., from about 0.05 weight percentto about 3 weight percent, from about 0.1 weight percent to about 3weight percent; e.g., about 1.4 weight percent) of (a″).

In certain embodiments, component (ii) includes from about 0.05 weightpercent to about 5 weight percent (e.g., from about 0.05 weight percentto about 3 weight percent, from about 0.1 weight percent to about 2weight percent; e.g., about 1.0 weight percent) of (a′″).

In certain embodiments, component (ii) includes from about 0.005 weightpercent to about 0.1 weight percent (e.g., from about 0.005 weightpercent to about 0.05 weight percent; e.g., about 0.02 weight percent)of (b″).

In certain embodiments, component (ii) includes from about 0.05 weightpercent to about 1 weight percent (e.g., from about 0.05 weight percentto about 0.5 weight percent; e.g., about 0.20 weight percent) of (b′″).

In certain embodiments, component (ii) includes from about 0.05 weightpercent to about 1 weight percent (e.g., from about 0.05 weight percentto about 0.5 weight percent; e.g., about 0.15 weight percent) of (c″).

In certain embodiments, component (ii) includes from about 0.005 weightpercent to about 0.5 weight percent (e.g., from about 0.005 weightpercent to about 0.3 weight percent; e.g., about 0.15 weight percent) of(c′″).

In certain of these embodiments, each of (a″)-(c′) is present.

In certain embodiments, component (ii) includes water (up to 100%) andthe ingredients and amounts as shown in Table 9.

TABLE 9 Ingredient Weight Percent methyl cellulose 0.05 weight percentto about 5 weight (Methocel A15C premium) percent (e.g., from about 0.05weight percent to about 3 weight percent, from about 0.1 weight percentto about 3 weight percent; e.g., about 1.4 weight percent Povidone(Kollidon K30) 0.05 weight percent to about 5 weight percent (e.g., fromabout 0.05 weight percent to about 3 weight percent, from about 0.1weight percent to about 2 weight percent; e.g., about 1.0 weight percentpropyl 4-hydroxybenzoate about 0.005 weight percent to about 0.1 weightpercent (e.g., from about 0.005 weight percent to about 0.05 weightpercent; e.g., about 0.02 weight percent) methyl 4-hydroxybenzoate about0.05 weight percent to about 1 weight percent (e.g., from about 0.05weight percent to about 0.5 weight percent; e.g., about 0.20 weightpercent) disodium phosphate about 0.05 weight percent to about 1dodecahydrate weight percent (e.g., from about 0.05 weight percent toabout 0.5 weight percent; e.g., about 0.15 weight percent) sodiumdihydrogen about 0.005 weight percent to about 0.5 phospahate dihydrateweight percent (e.g., from about 0.005 weight percent to about 0.3weight percent; e.g., about 0.15 weight percent)

In certain embodiments, component (ii) includes water (up to 100%) andthe ingredients and amounts as shown in Table 10.

TABLE 10 Ingredient Weight Percent methyl cellulose about 1.4 weightpercent (Methocel A15C premium) Povidone (Kollidon K30) about 1.0 weightpercent propyl 4-hydroxybenzoate about 0.02 weight percent methyl4-hydroxybenzoate about 0.20 weight percent disodium phosphatedodecahydrate about 0.15 weight percent sodium dihydrogen phospahatedihydrate about 0.15 weight percent

Ready-to-use” enemas are generally be provided in a “single-use” sealeddisposable container of plastic or glass. Those formed of a polymericmaterial preferably have sufficient flexibility for ease of use by anunassisted patient. Typical plastic containers can be made ofpolyethylene. These containers may comprise a tip for directintroduction into the rectum. Such containers may also comprise a tubebetween the container and the tip. The tip is preferably provided with aprotective shield which is removed before use. Optionally the tip has alubricant to improve patient compliance.

In some embodiments, the enema formulation (e.g., suspension) is pouredinto a bottle for delivery after it has been prepared in a separatecontainer. In certain embodiments, the bottle is a plastic bottle (e.g.,flexible to allow for delivery by squeezing the bottle), which can be apolyethylene bottle (e.g., white in color). In some embodiments, thebottle is a single chamber bottle, which contains the suspension orsolution. In other embodiments, the bottle is a multichamber bottle,where each chamber contains a separate mixture or solution. In stillother embodiments, the bottle can further include a tip or rectalcannula for direct introduction into the rectum. In some embodiments,the enema formulation can be delivered in the device shown in WO2017/040864 which is incorporated herein by reference in its entirety.The device includes a plastic bottle, a breakable capsule, and a rectalcannula and single flow pack.

Ocular Delivery

In some embodiments, niclosamide, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition thereof is suitable for localand topical administration to the eye (e.g., eye drops, ocularointments, ocular gels, contact lenses, and opthalamic inserts). See,e.g., Dubald et al. Pharmaceutics. 2018; 10(1): 10 and Patel et al.World J Pharmacol. 2013; 2(2): 47-64. In some embodiments, compositionssuitable for ocular delivery include in situ gelling systems, liposomes,nanoparticles, niosomes, nanoemulsions, and microemulsions Ocularcompositions can include, without limitation, one or more of any of thefollowing: viscogens (e.g., polyvinylalcohol (PVA),hydroxylmethylcellulose, hydroxylethylcellulose carboxymethylcellulose,glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g.,pluronic (triblock copolymers), cyclodextrins); preservatives (e.g.,benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol,sorbitol, and zinc chloride; Alcon Laboratories, Inc.), purite(stabilized oxychloro complex; Allergan, Inc.)); permeation enhancers(e.g., polyoxyethylene glycol ester and ethylenediaminetetra acetic acidsodium salt); and lubricants. In some embodiments, a composition forocular delivery is isotonic.

In some embodiments, an ocular ointment includes non-aqueous excipients.In some embodiments, an ocular ointment has an oleaginous base, anabsorption base, a water-removable base, or a water soluble base. Anoleaginous base can be a lipophilic ointment. For example, an oleaginousbase can include petrolatum and white ointment. An adsorption base canbe used as emollient. For example, an adsorption base can includelanolin, fatty alcohol and petrolatum. A water-soluble base can includeonly water soluble excipients such as macrogol with high molecularweight. A water removable base includes compositions that are an oil inwater emulsion.

In some embodiments, an ocular gel is a hydrogel. For example, apreformed gel or a composition that forms a gel in situ. Hydrogels caninclude polymers such as methylcellulose, hydroxylethylcellulose, sodiumhyaluronate, sodium alginate, povidone, polyvinylalcohol, celluloseacetate and derivatives, carbomer, magrogol, pseudolatex,polymethacrylic acid, alginate sodium, gellan gum (GELRITE®), pluronics,poly(n-isopropyl acrylamide), oly(acrylic acid), polyacrylamide,poloxamer, chitosan, and hydroxyl propyl methyl cellulose.

Other Forms of Delivery

In some embodiments, the chemical entities described herein or apharmaceutical composition thereof are suitable for local and topicaladministration to the eye (e.g., eye drops). Ocular compositions caninclude, without limitation, one or more of any of the following:viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone,Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers),Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia(boric acid, propylene glycol, sorbitol, and zinc chloride; AlconLaboratories, Inc.), Purite (stabilized oxychloro complex; Allergan,Inc.)).

In some embodiments, the chemical entities described herein or apharmaceutical composition thereof are suitable for local and topicaladministration to skin (e.g., ointments and creams). Ointments aresemisolid preparations that are typically based on petrolatum or otherpetroleum derivatives. Creams containing the selected active agent aretypically viscous liquid or semisolid emulsions, often eitheroil-in-water or water-in-oil. Cream bases are typically water-washable,and contain an oil phase, an emulsifier and an aqueous phase. The oilphase, also sometimes called the “internal” phase, is generallycomprised of petrolatum and a fatty alcohol such as cetyl or stearylalcohol; the aqueous phase usually, although not necessarily, exceedsthe oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic or amphoteric surfactant. As with other carriers or vehicles,an ointment base should be inert, stable, nonirritating andnon-sensitizing.

Dosages

The dosages may be varied depending on the requirement of the patient,the severity of the condition being treating and the particular compoundbeing employed. Determination of the proper dosage for a particularsituation can be determined by one skilled in the medical arts. Thetotal daily dosage may be divided and administered in portionsthroughout the day or by means providing continuous delivery.

In some embodiments, a niclsamide compound is administered isadministered at a dosage of from about 0.01 mg/Kg to about 200 mg/Kg(e.g., from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kgto about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg;from about 0.1 mg/Kg to about 200 mg/Kg; from about 0.1 mg/Kg to about150 mg/Kg; from about 0.1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kgto about 50 mg/Kg; from about 0.1 mg/Kg to about 10 mg/Kg; from about0.1 mg/Kg to about 5 mg/Kg).

In certain embodiments, the niclosamide compound is administered at adosage of from about 15 mg/Kg to about 100 mg/Kg (e.g., from about 15mg/Kg to about 90 mg/Kg, from about 20 mg/Kg to about 100 mg/Kg; fromabout 20 mg/Kg to about 90 mg/Kg; from about 20 mg/Kg to about 80 mg/Kg;from about 30 mg/Kg to about 90 mg/Kg; from about 30 mg/Kg to about 80mg/Kg; from about 35 mg/Kg to about 75 mg/Kg; from about 10 mg/Kg toabout 50 mg/Kg; from about 15 mg/Kg to about 45 mg/Kg; e.g., about 35mg/Kg or about 75 mg/Kg). In other embodiments, the chemical entity isadministered at a dosage of from about 0.1 mg/Kg to about 10 mg/Kg(e.g., from about 0.1 mg/Kg to about 5 mg/Kg; from about 1 mg/Kg toabout 10 mg/Kg; from about 1 mg/Kg to about 5 mg/Kg).

In some embodiments, formulations include from about 0.5 mg to about2500 mg (e.g., from about 0.5 mg to about 2000 mg, from about 0.5 mg toabout 1000 mg, from about 0.5 mg to about 750 mg, from about 0.5 mg toabout 600 mg, from about 0.5 mg to about 500 mg, from about 0.5 mg toabout 400 mg, from about 0.5 mg to about 300 mg, from about 0.5 mg toabout 200 mg; e.g., from about 5 mg to about 2500 mg, from about 5 mg toabout 2000 mg, from about 5 mg to about 1000 mg; from about 5 mg toabout 750 mg; from about 5 mg to about 600 mg; from about 5 mg to about500 mg; from about 5 mg to about 400 mg; from about 5 mg to about 300mg; from about 5 mg to about 200 mg; e.g., from about 50 mg to about2000 mg, from about 50 mg to about 1000 mg, from about 50 mg to about750 mg, from about 50 mg to about 600 mg, from about 50 mg to about 500mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg,from about 50 mg to about 200 mg; e.g., from about 100 mg to about 2500mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1000mg, from about 100 mg to about 750 mg, from about 100 mg to about 700mg, from about 100 mg to about 600 mg, from about 100 mg to about 500mg, from about 100 mg to about 400 mg, from about 100 mg to about 300mg, from about 100 mg to about 200 mg; e.g., from about 150 mg to about2500 mg, from about 150 mg to about 2000 mg, from about 150 mg to about1000 mg, from about 150 mg to about 750 mg, from about 150 mg to about700 mg, from about 150 mg to about 600 mg, from about 150 mg to about500 mg, from about 150 mg to about 400 mg, from about 150 mg to about300 mg, from about 150 mg to about 200 mg; e.g., from about 150 mg toabout 500 mg; e.g., from about 300 mg to about 2500 mg, from about 300mg to about 2000 mg, from about 300 mg to about 1000 mg, from about 300mg to about 750 mg, from about 300 mg to about 700 mg, from about 300 mgto about 600 mg; e.g., from about 400 mg to about 2500 mg, from about400 mg to about 2000 mg, from about 400 mg to about 1000 mg, from about400 mg to about 750 mg, from about 400 mg to about 700 mg, from about400 mg to about 600 from about 400 mg to about 500 mg; e.g., 150 mg or450 mg) of the niclosamide compound.

In certain embodiments, formulations include from about 50 mg to about250 mg (e.g., from about 100 mg to about 200; e.g., about 150 mg) of theniclosamide compound.

The foregoing dosages can be administered on a daily basis (e.g., as asingle dose per day; or as two or more divided doses per day; or a twoor more doses; e.g., two doses per day) or non-daily basis (e.g., everyother day, every two days, every three days, once weekly, twice weeks,once every two weeks, once a month). In certain embodiments, dosages canbe administered for about 1 week, about 2 weeks, about 3 weeks, about 4weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about3 months, about 6 months, about 1 year, or beyond. For example, dosages(e.g., about 2.5 mg/mL or about 7.5 mg/mL) of the chemical entity inliquid carrier can be administered twice a day on a daily basis forabout 6 weeks. In certain of these embodiments, the chemical entity isniclosamide, or a pharmaceutically acceptable salt and/or hydrate and/orcocrystal thereof. For example, about 2.5 mg/mL or about 7.5 mg/mL ofniclosamide in liquid carrier can be administered twice a day on a dailybasis for about 6 weeks. Representative liquid carriers include, e.g.,those previously described in conjunction with component (ii).

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

What is claimed is:
 1. A method of treating a symptom associated with aCOVID-19 viral infection in a subject diagnosed as having a COVID-19viral infection and exhibiting the symptom at the time of treatment, themethod comprising: administering to the respiratory system of thesubject a composition comprising an effective amount of a compoundcomprising niclosamide:

or a pharmaceutically acceptable salt, hydrate, or co-crystal thereof,to the subject so as to treat the symptom in the subject diagnosed ashaving the COVID-19 viral infection.
 2. The method of claim 1, whereinthe symptom is a digestive symptom.
 3. The method of claim 1, whereinthe symptom is a respiratory symptom.
 4. The method of claim 1, whereinthe compound is crystalline.
 5. The method of claim 1, wherein thecompound comprises niclosamide ethanolamine.
 6. The method of claim 1,wherein the composition further comprises one or more pharmaceuticallyacceptable excipients independently selected from thickeners, viscosityenhancing agents, bulking agents, mucoadhesive agents, penetrationenhancers, buffers, preservatives, diluents, binders, lubricants,glidants, disintegrants, fillers, solubilizing agents, pH modifyingagents, preservatives, stabilizing agents, anti-oxidants, wetting oremulsifying agents, suspending agents, pigments, colorants, isotonicagents, chelating agents, emulsifiers, and diagnostic agents.
 7. Themethod of claim 1, wherein the composition further comprises: apolyvinylpyrrolidone; and a beta cyclodextrin.
 8. The method of claim 1,wherein the composition further comprises sodium salicylate, citricacid, one or more chitosans, one or more phospholipids, one or morefatty acids, one or more fatty acid esters, glycerol, or combinationsthereof.
 9. The method of claim 1, wherein the composition isadministered by inhalation.
 10. The method of claim 1, wherein thecomposition is administered intranasally.
 11. The method of claim 1,wherein the composition has a particle size distribution D(0.9) of fromabout 1.0 μm to about 10.0 μm.
 12. The method of claim 1, wherein theadministering comprises topically or locally administering thecomposition to the lungs of the subject.
 13. The method of claim 1,wherein the composition is administered with an inhalation deviceselected from a nebulizer, a metered dose inhaler, a dry powder inhaler,a jet nebulizer, an ultrasonic wave nebulizer, a heat vaporizer, a softmist inhaler, a thermal aerosol inhaler, or an electrohydrodynamic-basedsolution misting inhaler.
 14. The method of claim 1, wherein thecomposition is administered intranasally by a spray, an ointment, or agel.
 15. The method of claim 1, wherein the composition furthercomprises nanoparticles, spray dried materials, engineered porousparticles, liposomes, or combinations thereof.
 16. The method of claim1, wherein the symptom appears from 2-14 days after the subject'sexposure to coronavirus.